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Pharmacogenetic Results: Clinical Implications and Recommendations

These pharmacogenetic clinical implications and recommendations are based on the Clinical Pharmacogenetic Implementation Consortium (CPIC) Guidelines, FDA Table of Pharmacogenetic Associations, and FDA labeling. The pharmacogenetic results and accompanying clinical implications and therapeutic recommendations predict the function of drug metabolizing enzymes, drug transporters, and drug target proteins based on the genetic variants that encode these proteins.

Note: This information is based on genotype alone and does not consider possible phenoconversion. Phenoconversion occurs when a patient is taking a medication that induces or inhibits the drug metabolizing enzyme, which can change the predicted phenotype.

Pharmacogenetic test results, their predicted clinical implications, and recommendations should be used as a tool and one piece of information along with other patient-specific factors (e.g., renal function, hepatic function, sex, environment, comorbid diseases) to make prescribing decisions.

CYP2D6, CYP2C19 and Tertiary Amine Tricyclic Antidepressants (TCAs): Amitriptyline, Clomipramine, Doxepin, Imipramine, Trimipramine

These recommendations only apply when using higher doses for treatment of conditions such as depression. For neuropathic pain where lower doses are used, no dose modifications are recommended, however intermediate and poor metabolizers may have increased risk of side effects and ultra rapid metabolizers have an increased risk of failing therapy. Evidence for these recommendations is primarily based on amitriptyline evidence, but because of comparable pharmacokinetics, it is reasonable to apply to other tertiary amines as well.

Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the table below.

If either CYP2D6 or CYP2C19 genotypes are unavailable, scroll down in this table to the “Instructions for Unavailable Genotypes”.

Important Instructions: Please use CYP2D6 Activity Score to select the appropriate column and then CYP2C19 phenotype to select the appropriate row in the table below. 

CYP2D6 Ultra Rapid Metabolizer

 

Increased CYP2D6 enzyme activity.


Increased risk of treatment failure based on CYP2D6 alone.

CYP2D6 Normal – Ultra Rapid Metabolizer*

 

Normal to increased CYP2D6 enzyme activity.


Possible increased risk of treatment failure based on CYP2D6 alone.

CYP2D6 Normal Metabolizer*


Normal CYP2D6 enzyme activity.

 
Normal response expected based on CYP2D6 alone.

CYP2D6 Intermediate Metabolizer*


Decreased CYP2D6 enzyme activity.

 
Increased risk of adverse effects (e.g., anticholinergic, CNS, and cardiac) based on CYP2D6 alone.

CYP2D6 Poor Metabolizer


No CYP2D6 enzyme activity.

 
Increased risk of adverse effects (e.g., anticholinergic, CNS, and cardiac) based on CYP2D6 alone.

CYP2C19 Ultra Rapid Metabolizer


Increased CYP2C19 enzyme activity.

 
Increased conversion to secondary amines which may affect response or adverse effects (e.g., anticholinergic, CNS, and cardiac) based on CYP2C19 alone.

Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments.

Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments.

Consider alternative not metabolized by CYP2C19 e.g., secondary amine TCA (i.e., nortriptyline, desipramine).

Consider alternative not metabolized by CYP2C19 e.g., secondary amine TCA (i.e., nortriptyline, desipramine).

Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments.

CYP2C19 Rapid Metabolizer


Increased CYP2C19 enzyme activity.

 
Increased conversion to secondary amines which may affect response or adverse effects (e.g., anticholinergic, CNS, and cardiac) based on CYP2C19 alone.

Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments.

Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments.

Consider alternative not metabolized by CYP2C19 e.g., secondary amine TCA (i.e., nortriptyline, desipramine).

Consider alternative not metabolized by CYP2C19 e.g., secondary amine TCA (i.e., nortriptyline, desipramine).

Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments.

CYP2C19 Normal Metabolizer


Normal CYP2C19 enzyme activity.

 
Normal response expected based on CYP2C19 alone.

Avoid use of tertiary amines or if warranted, titrate to higher target dose.

Avoid use of tertiary amines or if warranted, titrate to higher target dose.

Use standard doses of tertiary amines.

Decrease dose by 25%.

Avoid use of tertiary amines or if warranted, decrease dose by 50%.

CYP2C19 Intermediate Metabolizer


Decreased CYP2C19 enzyme activity.


Reduced conversion to secondary amines but normal response expected based on CYP2C19 alone.

Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments.

Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments.

Use standard doses of tertiary amines.

Decrease dose by 25%, utilize therapeutic drug monitoring to guide dose adjustments.

Avoid use of tertiary amines or if warranted, decrease dose by 50%, utilize therapeutic drug monitoring to guide dose adjustments.

CYP2C19 Poor Metabolizer


No CYP2C19 enzyme activity.


Greatly reduced conversion to secondary amines, which may affect response or adverse effects (e.g., anticholinergic, CNS, and cardiac) based on CYP2C19 alone

Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments.

Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments.

Avoid use of tertiary amines or if warranted, decrease dose by 50%.

Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments.

Avoid use of tertiary amines or if warranted, utilize therapeutic drug monitoring to guide dose adjustments.

Instructions for Unavailable Genotypes

If for CYP2C19 either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or CYP2C19 was not genotyped, but CYP2D6 is available, follow across the CYP2C19 Normal Metabolizer row to the appropriate CYP2D6 phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable CYP2C19 genotype; consider testing or repeat testing of CYP2C19 as appropriate.

 
If for CYP2D6 either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or CYP2D6 was not genotyped, but CYP2C19 is available, follow down the CYP2D6 Normal Metabolizer column to the appropriate CYP2C19 phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable CYP2D6 genotype; consider testing or repeat testing of CYP2D6 as appropriate.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Resources

Reference: Hicks JK et al. Clin Pharmacol Ther. 2017 Jul;102(1):37-44. PMID: 27997040.

*Some laboratories have started calling activity scores of 1.0 as Intermediate Metabolizers, however they are still classified as Normal Metabolizers with UF Health Pathology.

CYP2D6 and Atomoxetine

Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the table below.

CYP2D6 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

Ultra Rapid Metabolizer
(Activity Score >2.0)

Increased CYP2D6 enzyme activity.

 
For children and adults:  Increased risk of treatment failure.

For children: Use standard dose and titrations of atomoxetine, if no response nor adverse effects after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml up to either 1.4 mg/kg/day or 100 mg/day, whichever is less.

 
For adults: Use standard dose and titrations of atomoxetine, if no response after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml. Dosages above the maximum 100 mg/day may be needed to achieve target concentrations, though >120 mg/day has not been evaluated.

Normal – Ultra Rapid Metabolizer with an enzyme
Activity Score 1+, 1.5+, or 2+*

Normal to increased CYP2D6 enzyme activity.


For children and adults:
Increased risk of treatment failure

For children: Use standard dose and titrations of atomoxetine, if no response nor adverse effects after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml up to either 1.4 mg/kg/day or 100 mg/day, whichever is less.


For adults: Use standard dose and titrations of atomoxetine, if no response after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml. Dosages above the maximum 100 mg/day may be needed to achieve target concentrations, though >120 mg/day has not been evaluated.

Normal Metabolizer  with an enzyme Activity Score of 1.5-2.0*

Normal CYP2D6 enzyme activity.


For children and adults:

Increased risk of treatment failure.

For children: Use standard dose and titrations of atomoxetine, if no response nor adverse effects after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml up to either 1.4 mg/kg/day or 100 mg/day, whichever is less.

 
For adults: Use standard dose and titrations of atomoxetine, if no response after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml. Dosages above the maximum 100 mg/day may be needed to achieve target concentrations, though >120 mg/day has not been evaluated.

Normal Metabolizer  with an enzyme Activity Score of 1.0*

Normal CYP2D6 enzyme activity.


For children and adults:
Increased risk of treatment failure

For children: Use standard dose and titrations of atomoxetine, if no response nor adverse effects after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml up to either 1.4 mg/kg/day or 100 mg/day, whichever is less.

 
For adults: Use standard dose and titrations of atomoxetine, if no response after 2 weeks, consider obtaining a peak plasma concentration (1–2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/ml. Dosages above the maximum 100 mg/day may be needed to achieve target concentrations, though >120 mg/day has not been evaluated.

Intermediate Metabolizer
(Activity Score 0.25-0.75)*

Decreased CYP2D6 enzyme activity.


For children and adults:
Increased risk of adverse effects (e.g., increase in HR and DBP) leading to increased risk of treatment discontinuation.

For children: Initiate with standard dose (0.5 mg/kg/day) and maintain dose instead of titrating after 3 days, if no response nor adverse effects after 2 weeks, consider obtaining a plasma concentration (2–4 hours after dose administered). If < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/ml. Reduce dose if experiencing unacceptable adverse effects.

 
For adults: Initiate with standard dose (40 mg/day) and titrate dose after 2 weeks (instead of 3 days) to 80 mg/day if no response.  If response is inadequate after additional 2 weeks, consider obtaining a plasma concentration (2–4 hours after dose administered). If < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/ml. Reduce dose if experiencing unacceptable side effects.

Poor Metabolizer
(Activity Score 0)

No CYP2D6 enzyme activity.


For children and adults:
Increased effectiveness of treatment and increased risk of adverse effects (e.g., increase in HR and DBP).

PMs will likely require lower doses


For children: Initiate with standard dose (0.5 mg/kg/day) and maintain dose instead of titrating after 3 days, if no response nor adverse effects after 2 weeks, consider obtaining a plasma concentration (2–4 hours after dose administered). If < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/ml. Reduce dose if experiencing unacceptable adverse effects. 

 
For adults: Initiate with standard dose (40 mg/day) and titrate dose after 2 weeks (instead of 3 days) to 80 mg/day if no response.  If response is inadequate after additional 2 weeks, consider obtaining a plasma concentration (2–4 hours after dose administered). If < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/ml. Reduce dose if experiencing unacceptable side effects.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Reference: Brown JT et al. Clin Pharmacol Ther. 2019 Jul;106(1):94-102. PMID: 30801677.

*Some laboratories have started calling activity scores of 1.0 as Intermediate Metabolizers, however they are still classified as Normal Metabolizers with UF Health Pathology.

SLCO1B1 and Atorvastatin

To compare statin-associated musculoskeletal symptoms (SAMS) by statin intensities with doses for SLCO1B1 decreased and poor function to guide alternative statin selection, click here. For recommendations for patients on existing statin therapy, see footnote below table*

SLCO1B1 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

SLCO1B1 Increased Function

Increased SLCO1B1 transporter function.

 
Normal myopathy risk expected.

Initiate standard dosing.

SLCO1B1 Normal Function

Normal SLCO1B1 transporter function.

 
Normal myopathy risk expected.

Initiate standard dosing.

SLCO1B1 Decreased Function

Decreased SLCO1B1 transporter function.


Moderate risk of statin-induced myopathy with 40 mg.


High risk of statin-induced myopathy with 80 mg.

Initiate ≤ 40 mg, if a dose > 40 mg is needed, consider combination therapy.

SLCO1B1 Poor Function

No SLCO1B1 transporter function.

 
High risk of statin-induced myopathy with 40-80 mg.

Initiate ≤ 20mg, if a dose > 20mg is needed, consider rosuvastatin (≤ 20mg) or combination therapy.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be dtermined at this time. 

Reference: Cooper-DeHoff RM et al. Clin Pharmacol Ther. 2022 May;111(5):1007-1021. PMID: 35152405.

*Recommendations for patients on existing statin therapy:

For patients who are currently taking a statin with moderate risk of statin-induced myopathy, if the statin has been continued at a stable dose for 4 weeks without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than 4 weeks clinicians can consider changing the statin or dose to a regimen with lower risk that meets the appropriate guideline recommended intensity.

For patients who are currently taking a statin with high risk of statin-induced myopathy, if the statin has been continued at a stable dose for at least 1 year without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than one year clinicians can consider changing the statin or dose to regimen with lower risk that meets the appropriate guideline recommended intensity.

To see statins with moderate and high risk of statin-induced myopathy, click here.

TPMT, NUDT15 and Azathioprine

If either TPMT or NUDT15 genotypes are unavailable, scroll down in this table to the “Instructions for Unavailable Genotypes”.

TPMT Normal Metabolizer


Normal TPMT enzyme activity.

 
Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on TPMT alone.

TPMT Intermediate Metabolizer


Decreased TPMT enzyme activity.

 
Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on TPMT alone.

TPMT Poor – Intermediate Metabolizer


Decreased to no TPMT enzyme activity.

 
Increased to greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on TPMT alone.

TPMT Poor Metabolizer


No TPMT enzyme activity.

 
Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on TPMT alone.

NUDT15 Normal Metabolizer


Normal NUDT15 enzyme activity.

 
Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on NUDT15 alone.

Start with normal starting dose per disease-specific guidelines. Allow 2 weeks to reach steady-state after each dose adjustment.

Reduce starting doses by 30–80%. Allow 2–4 weeks to reach steady-state after each dose adjustment.

For malignant conditions:
Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions:
Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

NUDT15 Intermediate Metabolizer


Decreased NUDT15 enzyme activity.

 
Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on NUDT15 alone.

Reduce starting doses by 30-80%. Allow 2–4 weeks to reach steady-state after each dose adjustment.

Reduce starting doses by 30-80%. Allow 2–4 weeks to reach steady-state after each dose adjustment.


Due to the additive effect of both genes may require further dose reduction.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment.


For nonmalignant conditions:

Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment.


For nonmalignant conditions:

Consider alternative nonthiopurine immunosuppressant therapy.

NUDT15 Poor – Intermediate Metabolizer


Decreased to no NUDT15 enzyme activity.

 
Increased to greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on NUDT15 alone.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold). Allow 4–6 weeks to reach steady-state after each dose adjustment.


For nonmalignant conditions:

Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold). Allow 4–6 weeks to reach steady-state after each dose adjustment.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment.


For nonmalignant conditions:

Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment.


For nonmalignant conditions:

Consider alternative nonthiopurine immunosuppressant therapy.

NUDT15 Poor Metabolizer


No NUDT15 enzyme activity.

 
Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on NUDT15 alone.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold). Allow 4–6 weeks to reach steady-state after each dose adjustment.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold). Allow 4–6 weeks to reach steady-state after each dose adjustment.


For nonmalignant conditions:

Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

Instructions for Unavailable Genotypes

If for NUDT15 either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or NUDT15 was not genotyped, but TPMT is available, follow across the NUDT15 Normal Metabolizer row to the appropriate TPMT phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable NUDT15 genotype; consider testing or repeat testing of NUDT15 as appropriate.

 
If for TPMT either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or TPMT was not genotyped, but NUDT15 is available, follow down the TPMT Normal Metabolizer column to the appropriate NUDT15 phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable TPMT genotype; consider testing or repeat testing of TPMT as appropriate.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Resources

Reference: Relling MV et al. Clin Pharmacol Ther. 2019 May;105(5):1095-1105. PMID: 30447069.

DPYD and Capecitabine, Fluorouracil

DPYD Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

Normal Metabolizer

Normal DPD enzyme activity.

 
Normal response expected.

Use standard dose of fluoropyrimidines.

Intermediate Metabolizer with an enzyme
Activity Score of 1.5

Decreased DPD enzyme activity.

 
Increased risk for severe or even fatal drug toxicity (e.g. neutropenia, diarrhea, stomatitis, mucositis, hand-foot syndrome).

Reduce starting dose by 50%, thereafter titrate dose based on toxicity tolerance or therapeutic drug monitoring.

Intermediate Metabolizer with an enzyme

Activity Score 1.0

Decreased DPD enzyme activity.

 
Increased risk for severe or even fatal drug toxicity (e.g. neutropenia, diarrhea, stomatitis, mucositis, hand-foot syndrome).

Reduce starting dose by 25 to 50%, thereafter titrate dose based on toxicity tolerance or therapeutic drug monitoring.

Poor Metabolizer with an enzyme
Activity Score of 0.5

Little to no DPD enzyme activity.


Very high risk for severe or even fatal drug toxicity (e.g. neutropenia, diarrhea, stomatitis, mucositis, hand-foot syndrome).

Avoid fluoropyrimidines and use alternative agent. If alternatives are not appropriate and phenotype testing is unavailable to estimate starting dose, may consider an initial dose reduction of 75% and utilize therapeutic drug monitoring.

Poor Metabolizer with an enzyme
Activity Score of 0

Little to no DPD enzyme activity.
Very high risk for severe or even fatal drug toxicity (e.g. neutropenia, diarrhea, stomatitis, mucositis, hand-foot syndrome).

Avoid fluoropyrimidines and use alternative agent.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Reference: Amstutz U et al. Clin Pharmacol Ther. 2018 Feb;103(2):210-216. PMID: 29152729.

CYP2C9 and Celecoxib, Flurbiprofen, Ibuprofen

CYP2C9 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

Normal Metabolizer (Normal Activity)

Normal CYP2C9 enzyme activity.

 
Normal response expected.

Initiate therapy with recommended starting dose.

 
In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

Intermediate Metabolizer (Decreased Activity) with an enzyme Activity Score of 1.5

Decreased CYP2C9 enzyme activity.


Slightly increased risk of adverse events (e.g., GI bleed, cardiovascular).

Initiate therapy with recommended starting dose. For ibuprofen, may consider initiating with a lower starting dose if CYP2C9 genotype includes *2.

 
In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

Intermediate Metabolizer (Decreased Activity) with an enzyme Activity Score 1.0

Decreased CYP2C9 enzyme activity.

 
Increased risk of adverse events (e.g., GI bleed, cardiovascular).

Initiate therapy with lowest starting dose and titrate dose upward to clinical effect or maximum recommended dose with caution. Additional caution should be implemented with ibuprofen if CYP2C9 genotype includes *2.

 
In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

Poor Metabolizer (Very Decreased Activity)

Little to no CYP2C9 enzyme activity.

 
Increased risk of adverse events (e.g., GI bleed, cardiovascular).

Initiate therapy with a 25-50% initial dose reduction and titrate slowly, up to 50% of the maximum recommended dose. Allow at least one week between dose titrations.


Alternatively, consider an alternate NSAID not metabolized by CYP2C9 (e.g., aspirin, ketorolac, naproxen, and sulindac).

 
In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Reference: Theken KN et al. Clin Pharmacol Ther. 2020 Aug;108(2):191-200. PMID: 32189324.


CYP2D6, CYP2C19 and SSRIs (Fluvoxamine, Paroxetine, Citalopram, Escitalopram, Sertraline), Vortioxetine, Venlafaxine

Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the table below. However, please note that several CYP2D6 inhibitors are SSRIs and will not cause self-inhibition that would warrant a treatment change (e.g., CYP2D6 Normal Metabolizer phenotype can still be followed to guide dosing of paroxetine).

If either CYP2D6 or CYP2C19 genotypes are unavailable, scroll down in this table to the “Instructions for Unavailable Genotypes”.

CYP2D6 Ultra Rapid Metabolizer

 
Increased CYP2D6 enzyme activity.

CYP2D6 Normal – Ultra Rapid Metabolizer*

 
Normal to increased CYP2D6 enzyme activity.

CYP2D6 Normal Metabolizer*


Normal CYP2D6 enzyme activity.

CYP2D6 Intermediate Metabolizer*


Decreased CYP2D6 enzyme activity.

CYP2D6 Poor Metabolizer


No CYP2D6 enzyme activity.

CYP2C19 Ultra Rapid Metabolizer

 
Increased CYP2C19 enzyme activity.

Clinical Implications:

Increased risk of treatment failure with paroxetine, escitalopram, citalopram, and sertraline.


Therapeutic Recommendation:

Avoid paroxetine, escitalopram, citalopram, and potentially sertraline;


AND
Consider fluoxetine or non-SSRI antidepressant (e.g., venlafaxine, duloxetine, bupropion, or others).

Clinical Implications:

Increased risk of treatment failure with escitalopram, citalopram, sertraline and possibly paroxetine.


Therapeutic Recommendation:

Avoid paroxetine, escitalopram, citalopram, and potentially sertraline;

AND
Consider fluoxetine or non-SSRI antidepressant (e.g., venlafaxine, duloxetine, bupropion, or others).

Clinical Implications:

Normal response expected with paroxetine, fluvoxamine, vortioxetine, and venlafaxine.  Increased risk of treatment failure with escitalopram, citalopram, and sertraline


Therapeutic Recommendation:

Avoid escitalopram, citalopram, and potentially sertraline;


AND

Consider non-CYP2C19 SSRI (i.e., paroxetine, fluoxetine, or fluvoxamine) as alternative because of patient’s CYP2D6 metabolizer status;

OR 

 Consider non-SSRI antidepressant (e.g., duloxetine, bupropion, venlafaxine).

Clinical Implications:

Slightly increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with paroxetine and fluvoxamine.  Increased risk of treatment failure with escitalopram, citalopram, and sertraline


Therapeutic Recommendation:

Avoid escitalopram, citalopram, and potentially sertraline;

AND

Consider non-CYP2C19 SSRI (i.e., paroxetine, fluoxetine, or fluvoxamine) as alternative because of patient’s CYP2D6 metabolizer status;

OR 

Consider non-SSRI antidepressant (e.g., duloxetine, bupropion, venlafaxine).

Clinical Implications:

Increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with paroxetine, fluvoxamine, vortioxetine, and venlafaxine.  Increased risk of treatment failure with escitalopram, citalopram, and sertraline


Therapeutic Recommendation:

Avoid paroxetine, fluvoxamine, and venlafaxine OR decrease dose by 50% if use is warranted;

AND

Avoid vortioxetine OR utilize with a maximum dose of 10 mg/day;

AND

Avoid escitalopram, citalopram, and potentially sertraline;

AND
Consider non-SSRI antidepressant (e.g., desvenlafaxine, duloxetine, bupropion, or others).

CYP2C19 Rapid Metabolizer

 
Increased CYP2C19 enzyme activity.

Clinical Implications:

Increased risk of treatment failure with paroxetine, escitalopram, citalopram, and sertraline.


Therapeutic Recommendation:

Avoid paroxetine, escitalopram, citalopram, and potentially sertraline;

AND


Consider fluoxetine or non-SSRI antidepressant (e.g., venlafaxine, duloxetine, bupropion, or others).

Clinical Implications:

Increased risk of treatment failure with escitalopram, citalopram, sertraline, and possibly paroxetine.


Therapeutic Recommendation:

Avoid paroxetine, escitalopram, citalopram, and potentially sertraline;

AND

Consider fluoxetine or non-SSRI antidepressant (e.g., venlafaxine, duloxetine, bupropion, or others).

Clinical Implications:

Normal response expected with paroxetine, fluvoxamine, vortioxetine, and venlafaxine.  Increased risk of treatment failure with escitalopram, citalopram, and sertraline


Therapeutic Recommendation:

Avoid escitalopram, citalopram, and potentially sertraline;

AND

Consider non-CYP2C19 SSRI (i.e., paroxetine, fluoxetine, or fluvoxamine) as alternative because of patient’s CYP2D6 metabolizer status;

OR 
 
Consider non-SSRI antidepressant (e.g., duloxetine, bupropion, venlafaxine).

Clinical Implications:

Slightly increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with paroxetine and fluvoxamine.  Increased risk of treatment failure with escitalopram, citalopram, and sertraline.


Therapeutic Recommendation:

Avoid escitalopram, citalopram, and potentially sertraline;


AND

Consider non-CYP2C19 SSRI (i.e., paroxetine, fluoxetine, or fluvoxamine) as alternative because of patient’s CYP2D6 metabolizer status;

OR 

Consider non-SSRI antidepressant (e.g., duloxetine, bupropion, venlafaxine).

Clinical Implications:

Increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with paroxetine, fluvoxamine, vortioxetine, and venlafaxine.  Increased risk of treatment failure with escitalopram, citalopram, and sertraline


Therapeutic Recommendation:

Avoid paroxetine, fluvoxamine, and venlafaxine OR decrease dose by 50% if use is warranted;

AND

Avoid vortioxetine OR utilize with a maximum dose of 10 mg/day;

AND

Avoid escitalopram, citalopram, and potentially sertraline;

AND

Consider non-SSRI antidepressant (e.g., desvenlafaxine, duloxetine, bupropion, or others).

CYP2C19 Normal Metabolizer

 
Normal CYP2C19 enzyme activity.

Clinical Implications:

Increased risk of treatment failure with paroxetine. Normal response expected with escitalopram, citalopram, and sertraline.


Therapeutic Recommendation:

Avoid paroxetine;

AND

Consider non-CYP2D6 SSRI (e.g., sertraline, escitalopram, or citalopram) as alternative because of patient’s CYP2C19 metabolizer status;

OR

Consider non-SSRI antidepressant (e.g., duloxetine, bupropion, venlafaxine).

Clinical Implications:

Possible increased risk of treatment failure with paroxetine. Normal response expected with escitalopram, citalopram, and sertraline.


Therapeutic Recommendation:

Avoid paroxetine;

AND

Consider non-CYP2D6 SSRI (e.g., sertraline, escitalopram, or citalopram) as alternative because of patient’s CYP2C19 metabolizer status;

OR

Consider non-SSRI antidepressant (e.g., duloxetine, bupropion, venlafaxine).

Clinical Implications:

Normal response expected with paroxetine, fluvoxamine, vortioxetine, venlafaxine, escitalopram, citalopram, and sertraline.


Therapeutic Recommendation:
Use these SSRIs, vortioxetine, and venlafaxine at standard doses.

Clinical Implications:

Slightly increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with paroxetine and fluvoxamine. Normal response expected with escitalopram, citalopram, and sertraline.


Therapeutic Recommendation:
Use these SSRIs, vortioxetine, and venlafaxine at standard doses.

Clinical Implications:

Increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with paroxetine and fluvoxamine. Normal response expected with escitalopram, citalopram, and sertraline.


Therapeutic Recommendation:

Avoid paroxetine, fluvoxamine, and venlafaxine OR decrease dose by 50% if use is warranted;

AND

Avoid vortioxetine OR utilize with a maximum dose of 10 mg/day;

AND

Consider non-CYP2D6 SSRI (e.g., sertraline, escitalopram, or citalopram) as alternative because of patient’s CYP2C19 metabolizer status;

OR

Consider non-SSRI antidepressant (e.g., desvenlafaxine, duloxetine, bupropion, or others).

CYP2C19 Intermediate Metabolizer

 
Decreased CYP2C19 enzyme activity.

Clinical Implications:

Increased risk of treatment failure with paroxetine. Slightly increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with escitalopram, citalopram, and sertraline.


Therapeutic Recommendation:

Avoid paroxetine;

AND

Consider non-CYP2D6 SSRI (e.g., sertraline, escitalopram, or citalopram) as alternative because of patient’s CYP2C19 metabolizer status;

OR

Consider non-SSRI antidepressant (e.g., duloxetine, bupropion, venlafaxine).

Clinical Implications:

Possible increased risk of treatment failure with paroxetine. Slightly increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with escitalopram, citalopram, and sertraline.


Therapeutic Recommendation:

Avoid paroxetine;

AND

Consider non-CYP2D6 SSRI (e.g., sertraline, escitalopram, or citalopram) as alternative because of patient’s CYP2C19 metabolizer status;
OR

Consider non-SSRI antidepressant (e.g., duloxetine, bupropion, venlafaxine).

Clinical Implications:

Normal response expected with paroxetine, fluvoxamine, vortioxetine, and venlafaxine.  Slightly increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with escitalopram, citalopram, and sertraline.


Therapeutic Recommendation:

Use these SSRIs, vortioxetine, and venlafaxine at standard doses.

Clinical Implications:

Slightly increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with paroxetine, fluvoxamine, escitalopram, citalopram, and sertraline.


Therapeutic Recommendation:

Use these SSRIs, vortioxetine, and venlafaxine at standard doses.

Clinical Implications:

Increased risk with paroxetine and fluvoxamine and slightly increased risk with escitalopram, citalopram, and sertraline of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias).


Therapeutic Recommendation:

Avoid paroxetine, fluvoxamine, and venlafaxine OR decrease dose by 50% if use is warranted;

AND

Avoid vortioxetine OR utilize with a maximum dose of 10 mg/day;

AND

Consider non-CYP2D6 SSRI (e.g., sertraline, escitalopram, or citalopram) as alternative because of patient’s CYP2C19 metabolizer status;

OR

Consider non-SSRI antidepressant (e.g., desvenlafaxine, duloxetine, bupropion, or others).

CYP2C19 Poor Metabolizer

 
No CYP2C19 enzyme activity.

Clinical Implications:

Increased risk of treatment failure with paroxetine. Increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with escitalopram, citalopram, and sertraline.


Therapeutic Recommendation:

Avoid sertraline, escitalopram, and citalopram OR decrease dose by 50% if use is warranted;

AND

Avoid paroxetine;

AND

Consider fluoxetine or non-SSRI antidepressant (e.g., venlafaxine, duloxetine, bupropion, or others).

Clinical Implications:

Possible increased risk of treatment failure with paroxetine. Increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with escitalopram, citalopram, and sertraline.


Therapeutic Recommendation:

Avoid sertraline, escitalopram, and citalopram OR decrease dose by 50% if use is warranted;

AND

Avoid paroxetine;

AND

Consider fluoxetine or non-SSRI antidepressant (e.g., venlafaxine, duloxetine, bupropion, or others).

Clinical Implications:

Normal response expected with paroxetine, fluvoxamine, vortioxetine, and venlafaxine.  Increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with escitalopram, citalopram, and sertraline.


Therapeutic Recommendation:

Avoid sertraline, escitalopram, and citalopram OR decrease dose by 50% if use is warranted;

AND

Consider non-CYP2C19 SSRI (i.e., paroxetine, fluoxetine, or fluvoxamine) as alternative because of patient’s CYP2D6 metabolizer status;

OR 

Consider non-SSRI antidepressant (e.g., duloxetine, bupropion, venlafaxine).

Clinical Implications:

Slightly increased risk with paroxetine and fluvoxamine and increased risk with  escitalopram, citalopram, and sertraline of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias).


Therapeutic Recommendation:

Avoid sertraline, escitalopram, and citalopram OR decrease dose by 50% if use is warranted;

AND

Consider non-CYP2C19 SSRI (i.e., paroxetine, fluoxetine, or fluvoxamine) as alternative because of patient’s CYP2D6 metabolizer status;

OR 

Consider non-SSRI antidepressant (e.g., duloxetine, bupropion, venlafaxine).

Clinical Implications:

Increased risk of adverse effects/events (e.g., insomnia, GI dysfunction, sexual dysfunction, arrythmias) with paroxetine, fluvoxamine, vortioxetine, venlafaxine, escitalopram, citalopram, and sertraline.


Therapeutic Recommendation:

Avoid sertraline, escitalopram, citalopram, paroxetine, fluvoxamine, venlafaxine OR decrease dose by 50% if use is warranted;

AND

Avoid vortioxetine OR utilize with a maximum dose of 10 mg/day;

AND

Consider non-SSRI antidepressant (e.g., desvenlafaxine, duloxetine, bupropion, or others).

Instructions for Unavailable Genotypes

If for CYP2C19 either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or CYP2C19 was not genotyped, but CYP2D6 is available, follow across the CYP2C19 Normal Metabolizer row to the appropriate CYP2D6 phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable CYP2C19 genotype; consider testing or repeat testing of CYP2C19 as appropriate.

 
If for CYP2D6 either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or CYP2D6 was not genotyped, but CYP2C19 is available, follow down the CYP2D6 Normal Metabolizer column to the appropriate CYP2C19 phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable CYP2D6 genotype; consider testing or repeat testing of CYP2D6 as appropriate.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Resources

*Some laboratories have started calling activity scores of 1.0 as Intermediate Metabolizers, however they are still classified as Normal Metabolizers with UF Health Pathology.

CYP2C19 and Clopidogrel

CYP2C19 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

Ultra Rapid Metabolizer

Increased CYP2C19 enzyme activity.

 
Higher platelet inhibition, though an association with increased risk of bleeding following PCI has not been observed.

Use standard dose of clopidogrel.*

Rapid Metabolizer

Increased CYP2C19 enzyme activity.

 
Modestly higher platelet inhibition, though an association with increased risk of bleeding following PCI has not been observed.

Use standard dose of clopidogrel.*

Normal Metabolizer

Normal CYP2C19 enzyme activity.

 
Normal response expected.

Use standard dose of clopidogrel.

Intermediate Metabolizer

Decreased CYP2C19 enzyme activity.

 
Reduced activation of clopidogrel and increased risk for major adverse cardiac and cerebrovascular events.

Avoid clopidogrel, if there are no contraindications use prasugrel (Effient) 10 mg daily OR use ticagrelor (Brilinta) 90 mg twice daily.*

Poor Metabolizer

No CYP2C19 enzyme activity.

 
Significantly reduced activation of clopidogrel and increased risk for major adverse cardiac and cerebrovascular events.

Avoid clopidogrel, if there are no contraindications use prasugrel (Effient) 10 mg daily OR use ticagrelor (Brilinta) 90 mg twice daily.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Reference: Lee CR et al. Clin Pharmacol Ther. 2022 Jan 16:10.1002/cpt.2526. PMID: 35034351.

*The majority of evidence supporting recommendations is in the setting of ACS and PCI.  For ultra rapid and rapid metabolizer predicted phenotypes there is limited evidence on clinical outcomes in neurovascular disease. For ultra rapid, rapid, and intermediate metabolizer predicted phenotypes there is limited evidence on clinical outcomes in non-ACS and non-PCI cardiovascular indications.

CYP2D6 and Codeine, Hydrocodone, Tramadol

Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the table below.

CYP2D6 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

Ultra Rapid Metabolizer

Increased CYP2D6 enzyme activity.

 
Increased risk of adverse events (e.g., respiratory depression, death), even at low doses.

Use non-opioid if possible.**

 
If opioid indicated, use alternative opioid such as morphine, hydromorphone, or oxymorphone, that is not affected by CYP2D6 genotype.**

Normal – Ultra Rapid Metabolizer*

Normal to increased CYP2D6 enzyme activity.

 
Possible increased risk of adverse events (e.g., respiratory depression, death), even at low doses.

Use non-opioid if possible.**

 
If opioid indicated, use alternative opioid such as morphine, hydromorphone, or oxymorphone, that is not affected by CYP2D6 genotype.**

Normal Metabolizer*

Normal CYP2D6 enzyme activity.

 
Normal response expected.

Use label recommended age-specific or weight-specific dosing.

Intermediate Metabolizer*

Decreased CYP2D6 enzyme activity.

 
Little to no pain relief expected.

Use non-opioid if possible.**

 
If opioid indicated, use alternative opioid such as morphine, hydromorphone, or oxymorphone, that is not affected by CYP2D6 genotype.**

Poor Metabolizer

No CYP2D6 enzyme activity.

 
Little to no pain relief expected.

Use non-opioid if possible.**

 
If opioid indicated, use alternative opioid such as morphine, hydromorphone, or oxymorphone, that is not affected by CYP2D6 genotype.**

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Reference: Crews KR et al., Clin Pharmacol Ther. 2021 Oct;110(4):888-896. PMID: 33387367.

*Some laboratories have started calling activity scores of 1.0 as Intermediate Metabolizers, however they are still classified as Normal Metabolizers with UF Health Pathology.

**There is less evidence for this recommendation for hydrocodone.

CYP2D6 and Secondary Amine Tricyclic Antidepressants (TCAs): Nortriptyline, Desipramine

These recommendations only apply when using higher doses for treatment of conditions such as depression. For neuropathic pain where lower doses are used, no dose modifications are recommended, however intermediate and poor metabolizers may have increased risk of side effects and ultra rapid metabolizers have an increased risk of failing therapy. Evidence for these recommendations is primarily based on nortriptyline evidence, but because of comparable pharmacokinetics, it is reasonable to apply to other secondary amines as well.

Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the table below.

CYP2D6 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

Ultra Rapid Metabolizer

Increased CYP2D6 enzyme activity.

 
Increased risk of treatment failure.

Avoid use of secondary amines or if warranted, titrate to higher target dose utilizing therapeutic drug monitoring.

Normal – Ultra Rapid Metabolizer*

Normal to increased CYP2D6 enzyme activity.


Possible increased risk of treatment failure.

Avoid use of secondary amines or if warranted, titrate to higher target dose utilizing therapeutic drug monitoring.

Normal Metabolizer*

Normal CYP2D6 enzyme activity.

 
Normal response expected.

Use standard doses of secondary amines 

Intermediate Metabolizer*

Decreased CYP2D6 enzyme activity.

 
Increased risk of adverse effects (e.g., anticholinergic, CNS, and cardiac).

Decrease dose by 25%, utilize therapeutic drug monitoring to guide dose adjustments.

Poor Metabolizer

No CYP2D6 enzyme activity.

 
Increased risk of adverse effects (e.g., anticholinergic, CNS, and cardiac).

Avoid use of secondary amines or if warranted, decrease dose by 50% and utilize therapeutic drug monitoring to guide dose adjustments.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Reference: Hicks JK et al. Clin Pharmacol Ther. 2017 Jul;102(1):37-44. PMID: 27997040.

*Some laboratories have started calling activity scores of 1.0 as Intermediate Metabolizers, however they are still classified as Normal Metabolizers with UF Health Pathology.

CYP2C19 and Omeprazole, Pantoprazole, Lansoprazole, Dexlansoprazole

CYP2C19 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

Ultra Rapid Metabolizer

Increased CYP2C19 enzyme activity.

 
Increased risk of treatment failure.

Increase PPI dose by 2 times the standard daily dose.

Rapid Metabolizer

Increased CYP2C19 enzyme activity.

 
Increased risk of treatment failure.

For H. pylori infection or erosive esophagitis, increase PPI dose by 1.5-2 times the standard daily dose.

 
For all other indications, initiate standard starting daily dose and increase dose for inadequate response.

Normal Metabolizer

Normal CYP2C19 enzyme activity.

 
Normal response expected, unless treating H. pylori or erosive esophagitis, then increased risk of treatment failure.

For H. pylori infection or erosive esophagitis, increase PPI dose by 1.5-2 times the standard daily dose.

 
For all other indications, initiate standard starting daily dose.

Intermediate Metabolizer

Decreased CYP2C19 enzyme activity.

 
Increased risk of adverse effects (e.g., infections, electrolyte imbalance, bone fractures) with chronic use (>12 weeks).

For chronic therapy, consider a 50% dose reduction once symptoms are controlled.

Poor Metabolizer

No CYP2C19 enzyme activity.

 
Increased risk of adverse effects (e.g., infections, electrolyte imbalance, bone fractures) with chronic use (>12 weeks).

For chronic therapy, consider a 50% dose reduction once symptoms are controlled.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Reference: Lima JJ et al. Clin Pharmacol Ther. 2021 Jun;109(6):1417-1423. PMID: 32770672.

CYP2B6 and Efavirenz

CYP2B6 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

Ultra Rapid Metabolizer

Increased CYP2B6 enzyme activity.

 
Slightly lower dose-adjusted trough concentrations.

Initiate efavirenz with standard dosing (600 mg/day).

Rapid Metabolizer

Increased CYP2B6 enzyme activity.

 
Slightly lower dose-adjusted trough concentrations.

Initiate efavirenz with standard dosing (600 mg/day).

Normal Metabolizer

Normal CYP2B6 enzyme activity.

 
Normal response expected.

Initiate efavirenz with standard dosing (600 mg/day).

Intermediate Metabolizer

Decreased CYP2B6 enzyme activity.

 
Increased risk of CNS adverse effects (e.g., insomnia, impaired concentration, psychosis, suicidal ideation, depression).

Initiate efavirenz with decreased dose of 400 mg/day and consider utilizing therapeutic drug monitoring, if available.

Poor Metabolizer

Little to no CYP2B6 enzyme activity.

 
Significantly increased risk of CNS adverse effects (e.g., insomnia, impaired concentration, psychosis, suicidal ideation, depression).

Initiate efavirenz with decreased dose of 400 or 200 mg/day and consider utilizing therapeutic drug monitoring, if available.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Reference: Desta Z et al. Clin Pharmacol Ther. 2019 Oct;106(4):726-733. PMID: 31006110.

SLCO1B1, CYP2C9 and Fluvastatin

To compare statin-associated musculoskeletal symptoms (SAMS) by statin intensities with doses for SLCO1B1 decreased and poor function to guide alternative statin selection, click here. For recommendations for patients on existing statin therapy, see footnote below table*

If either SLCO1B1 or CYP2C9 genotypes are unavailable, scroll down in this table to the “Instructions for Unavailable Genotypes”.

Predicted Phenotype

CYP2C9 Normal Metabolizer

(Normal activity)


Normal CYP2C9 enzyme activity

 
Normal response expected based on CYP2C9 alone.

CYP2C9 Intermediate Metabolizer

(Decreased activity)


Decreased CYP2C9 enzyme activity.

 
Potential for increased risk of myopathy based on CYP2C9 alone.

CYP2C9 Poor Metabolizer

(Very Decreased Activity)


Little to no CYP2C9 enzyme activity.

 
Potential for increased risk of myopathy based on CYP2C9 alone.

SLCO1B1 Increased Function


Increased SLCO1B1 transporter function.


Normal myopathy risk expected based on SLCO1B1 alone.

Initiate standard dosing.

Initiate ≤ 40 mg, if a dose >40 mg is needed, consider alternative statin or combination therapy.

Initiate ≤ 20 mg, if a dose >20 mg is needed, consider alternative statin or combination therapy.

SLCO1B1 Normal Function


Normal SLCO1B1 transporter function.


Normal myopathy risk expected based on SLCO1B1 alone.

Initiate standard dosing.

Initiate ≤ 40 mg, if a dose >40 mg is needed, consider alternative statin or combination therapy.

Initiate ≤ 20 mg, if a dose >20 mg is needed, consider alternative statin or combination therapy.

SLCO1B1 Decreased Function


Decreased SLCO1B1 transporter function.


Moderate risk of statin-induced myopathy with 80 mg based on SLCO1B1 alone.

Initiate standard dosing.

Initiate ≤ 20 mg, if a dose >20 mg is needed, consider alternative statin or combination therapy.

Initiate an alternative statin with lower myopathy risk based on SLCO1B1 (refer to figure to choose based on desired potency).

SLCO1B1 Poor Function


No SLCO1B1 transporter function.


Moderate risk of statin-induced myopathy with 80 mg based on SLCO1B1 alone.

Initiate ≤ 40 mg, if dose > 40 mg is needed, consider higher dose, alternative statin, or combination therapy.

Initiate an alternative statin with lower myopathy risk based on SLCO1B1 (refer to figure to choose based on desired potency).

Initiate an alternative statin with lower myopathy risk based on SLCO1B1 (refer to figure to choose based on desired potency).

Instructions for Unavailable Genotypes

If for SLCO1B1 either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or SLCO1B1 was not genotyped, but CYP2C9 is available, follow across the SLCO1B1 Normal Metabolizer row to the appropriate CYP2C9 phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable SLCO1B1 genotype; consider testing or repeat testing of SLCO1B1 as appropriate.

 
If for CYP2C9 either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or CYP2C9 was not genotyped, but SLCO1B1 is available, follow down the CYP2C9 Normal Metabolizer column to the appropriate SLCO1B1 phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable CYP2C9 genotype; consider testing or repeat testing of CYP2C9 as appropriate.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Resources

Reference: Cooper-DeHoff RM et al. Clin Pharmacol Ther. 2022 May;111(5):1007-1021. PMID: 35152405.

*Recommendations for patients on existing statin therapy:

For patients who are currently taking a statin with moderate risk of statin-induced myopathy, if the statin has been continued at a stable dose for 4 weeks without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than 4 weeks clinicians can consider changing the statin or dose to a regimen with lower risk that meets the appropriate guideline recommended intensity.

For patients who are currently taking a statin with high risk of statin-induced myopathy, if the statin has been continued at a stable dose for at least 1 year without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than one year clinicians can consider changing the statin or dose to regimen with lower risk that meets the appropriate guideline recommended intensity.

To see statins with moderate and high risk of statin-induced myopathy, click here.

CYP2C9 and Phenytoin, Fosphenytoin

CYP2C9 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

Normal Metabolizer (Normal Activity)

Normal CYP2C9 enzyme activity.

 
Normal response expected based on CYP2C9 genotype. Risk of SJS/TEN dependent on HLA-B*15:02 (not tested).

Use standard dose and adjust based on clinical factors.

Intermediate Metabolizer (Decreased Activity) with an enzyme Activity Score of 1.5

Decreased CYP2C9 enzyme activity.

 
Normal response expected based on CYP2C9 genotype. Risk of SJS/TEN dependent on HLA-B*15:02 (not tested).

Use standard dose and adjust based on clinical factors

Intermediate Metabolizer (Decreased Activity) with an enzyme Activity Score 1.0

Decreased CYP2C9 enzyme activity.

 
Increased risk of adverse effects (e.g., sedation, ataxia, dizziness, leukopenia, suicidal ideation). Risk of SJS/TEN dependent on HLA-B*15:02 (not tested).

Use standard initial or loading dose for first dose, then use a ~25% dose reduction for subsequent doses. Thereafter, adjust according to therapeutic drug monitoring, response, and adverse effects.

Poor Metabolizer (Very Decreased Activity)

Little to no CYP2C9 enzyme activity.

 
Increased risk of adverse effects (e.g., sedation, ataxia, dizziness, leukopenia, suicidal ideation). Risk of SJS/TEN dependent on HLA-B*15:02 (not tested).

Use standard initial or loading dose for first dose, then use a ~50% dose reduction for subsequent doses. Thereafter, adjust according to therapeutic drug monitoring, response, and adverse effects.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Reference: Karnes JH et al. Clin Pharmacol Ther. 2021 Feb;109(2):302-309. PMID: 32779747.

SLCO1B1 and Lovastatin

To compare statin-associated musculoskeletal symptoms (SAMS) by statin intensities with doses for SLCO1B1 decreased and poor function to guide alternative statin selection, click here. For recommendations for patients on existing statin therapy, see footnote below table*

SLCO1B1 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

SLCO1B1 Increased Function

Increased SLCO1B1 transporter function.


Normal myopathy risk expected.

Initiate standard dosing.

SLCO1B1 Normal Function

Normal SLCO1B1 transporter function.


Normal myopathy risk expected.

Initiate standard dosing.

SLCO1B1 Decreased Function

Decreased SLCO1B1 transporter function.      

Moderate risk of statin-induced myopathy with 20 mg.                            

High risk of statin-induced myopathy with 40-80 mg.

Consider an alternative statin associated with lower risk, if lovastatin is warranted, limit dose to ≤ 20 mg/day.

SLCO1B1 Poor Function

No SLCO1B1 transporter function.

 
High risk of statin-induced myopathy with 20-80 mg.

Consider an alternative statin associated with lower risk.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Reference: Cooper-DeHoff RM et al. Clin Pharmacol Ther. 2022 May;111(5):1007-1021. PMID: 35152405.

*Recommendations for patients on existing statin therapy:

For patients who are currently taking a statin with moderate risk of statin-induced myopathy, if the statin has been continued at a stable dose for 4 weeks without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than 4 weeks clinicians can consider changing the statin or dose to a regimen with lower risk that meets the appropriate guideline recommended intensity.

For patients who are currently taking a statin with high risk of statin-induced myopathy, if the statin has been continued at a stable dose for at least 1 year without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than one year clinicians can consider changing the statin or dose to regimen with lower risk that meets the appropriate guideline recommended intensity.

To see statins with moderate and high risk of statin-induced myopathy, click here.

CYP2C9 and Meloxicam

CYP2C9 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

Normal Metabolizer (Normal Activity)

Normal CYP2C9 enzyme activity.


Normal response expected.

Initiate therapy with recommended starting dose.

 
In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

Intermediate Metabolizer (Decreased Activity) with an enzyme Activity Score of 1.5

Decreased CYP2C9 enzyme activity.


Slightly increased risk of adverse events (e.g., GI bleed, cardiovascular).

Initiate therapy with recommended starting dose.

 
In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

Intermediate Metabolizer (Decreased Activity) with an enzyme Activity Score 1.0

Decreased CYP2C9 enzyme activity.

 
Increased risk of adverse events (e.g., GI bleed, cardiovascular).

Initiate therapy with a 50% initial dose reduction and titrate slowly, up to 50% of the maximum recommended dose. Allow at least one week between dose titrations.

OR

Choose an alternative non-NSAID pain medication not metabolized by CYP2C9 (e.g. acetaminophen).

OR

If an NSAID is indicated, ibuprofen, celecoxib, or flurbiprofen can be used at the lowest starting dose and titrated. Other NSAIDs not metabolized by CYP2C9 can be used at standard doses (e.g., aspirin, ketorolac, naproxen, and sulindac).


In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

Poor Metabolizer (Very Decreased Activity)

Little to no CYP2C9 enzyme activity.

 
Increased risk of adverse events (e.g., GI bleed, cardiovascular).

Choose an alternative non-NSAID pain medication not metabolized by CYP2C9 (e.g. acetaminophen)

OR

If an NSAID is indicated, ibuprofen, celecoxib, or flurbiprofen can be used with a 25-50% initial dose reduction and slow titration up to 50% of the maximum recommended dose. Other NSAIDs not metabolized by CYP2C9 can be used at standard doses (e.g., aspirin, ketorolac, naproxen, and sulindac).


In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Reference: Theken KN et al. Clin Pharmacol Ther. 2020 Aug;108(2):191-200. PMID: 32189324.

TPMT, NUDT15 and Mercaptopurine

If either TPMT or NUDT15 genotypes are unavailable, scroll down in this table to the “Instructions for Unavailable Genotypes”.

TPMT Normal Metabolizer


Normal TPMT enzyme activity.

 
Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on TPMT alone.

TPMT Intermediate Metabolizer


Decreased TPMT enzyme activity.

 
Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on TPMT alone.

TPMT Poor – Intermediate Metabolizer


Decreased to no TPMT enzyme activity.

 
Increased to greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on TPMT alone.

TPMT Poor Metabolizer


No TPMT enzyme activity.

 
Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on TPMT alone.

NUDT15 Normal Metabolizer


Normal NUDT15 enzyme activity.

 
Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on NUDT15 alone.

Start with normal starting dose per disease-specific guidelines. Allow 2 weeks to reach steady-state after each dose adjustment.

Reduce starting doses by 30–80%. Allow 2–4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents.


If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents.


For nonmalignant conditions:

Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

NUDT15 Intermediate Metabolizer


Decreased NUDT15 enzyme activity.

 
Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on NUDT15 alone.

Reduce starting doses by 30–80%. Allow 2–4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents.

 
If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended.

Reduce starting doses by 30–80%. Allow 2–4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents.


If normal starting dose is already < 75 mg/m2/day or < 1.5 mg/kg/day, dose reduction may not be recommended.

 
Due to the additive effect of both genes may require further dose reduction.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

NUDT15 Poor – Intermediate Metabolizer


Decreased to no NUDT15 enzyme activity.

 
Increased to greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on NUDT15 alone.

For malignant conditions: Initiate dose at 10 mg/m2/day. Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Initiate dose at 10 mg/m2/day. Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents.


For nonmalignant conditions:

Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents.


For nonmalignant conditions:

Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

NUDT15 Poor Metabolizer


No NUDT15 enzyme activity.

 
Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on NUDT15 alone.

For malignant conditions: Initiate dose at 10 mg/m2/day. Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents.


For nonmalignant conditions:

Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Initiate dose at 10 mg/m2/day. Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

Instructions for Unavailable Genotypes

If for NUDT15 either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or NUDT15 was not genotyped, but TPMT is available, follow across the NUDT15 Normal Metabolizer row to the appropriate TPMT phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable NUDT15 genotype; consider testing or repeat testing of NUDT15 as appropriate.

 
If for TPMT either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or TPMT was not genotyped, but NUDT15 is available, follow down the TPMT Normal Metabolizer column to the appropriate NUDT15 phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable TPMT genotype; consider testing or repeat testing of TPMT as appropriate.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Resources

Reference: Relling MV et al. Clin Pharmacol Ther. 2019 May;105(5):1095-1105. PMID: 30447069.

CYP2D6 and Ondansetron

Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the table below.

CYP2D6 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

Ultra Rapid Metabolizer
(Activity Score >2.0)

Increased CYP2D6 enzyme activity.

 
Increased risk of treatment failure (i.e., uncontrolled nausea and vomiting).

Select alternative 5-HT3 antagonist not metabolized by CYP2D6 (i.e., granisetron) or alternative anti-emetic as appropriate (e.g., promethazine).

Normal – Ultra Rapid Metabolizer
(Activity Score 1+, 1.5+, or 2+)*

Normal to increased CYP2D6 enzyme activity.

 
Possible increased risk of treatment failure (i.e., uncontrolled nausea and vomiting).

Select alternative 5-HT3 antagonist not metabolized by CYP2D6 (i.e., granisetron) or alternative anti-emetic as appropriate (e.g., promethazine).

Normal Metabolizer
(Activity Score 1.0 – 2.0)*

Normal CYP2D6 enzyme activity.

 
Normal response expected.

Use standard dose of ondansetron

Intermediate Metabolizer
(Activity Score 0.25 – 0.75)*

Decreased CYP2D6 enzyme activity.

 
 Insufficient evidence demonstrating clinical impact.

Use standard dose of ondansetron

Poor Metabolizer
(Activity Score 0)

No CYP2D6 enzyme activity.

 
Insufficient evidence demonstrating clinical impact.

Use standard dose of ondansetron.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Reference: Bell GC et al. Clin Pharmacol Ther. 2017 Aug;102(2):213-218. PMID: 28002639.

*Some laboratories have started calling activity scores of 1.0 as Intermediate Metabolizers, however they are still classified as Normal Metabolizers with UF Health Pathology.

CYP2C9 and Piroxicam

CYP2C9 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

Normal Metabolizer (Normal Activity)

Normal CYP2C9 enzyme activity.

 
Normal response expected.

Initiate therapy with recommended starting dose.


In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals

Intermediate Metabolizer (Decreased Activity) with an enzyme Activity Score of 1.5

Decreased CYP2C9 enzyme activity.

 
Slightly increased risk of adverse events (e.g., GI bleed, cardiovascular).

Initiate therapy with recommended starting dose.

 
In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

Intermediate Metabolizer (Decreased Activity) with an enzyme Activity Score 1.0

Decreased CYP2C9 enzyme activity.

 
Increased risk of adverse events (e.g., GI bleed, cardiovascular).

Choose an alternative non-NSAID pain medication not metabolized by CYP2C9 (e.g. acetaminophen)

OR

If an NSAID is indicated, ibuprofen, celecoxib, or flurbiprofen can be used at the lowest starting dose and titrated. Other NSAIDs not metabolized by CYP2C9 can be used at standard doses (e.g., aspirin, ketorolac, naproxen, and sulindac).


In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

Poor Metabolizer (Very Decreased Activity)

Little to no CYP2C9 enzyme activity.

 
Increased risk of adverse events (e.g., GI bleed, cardiovascular).

Choose an alternative non-NSAID pain medication not metabolized by CYP2C9 (e.g. acetaminophen)

OR

If an NSAID is indicated, ibuprofen, celecoxib, or flurbiprofen can be used with a 25-50% initial dose reduction and slow titration up to 50% of the maximum recommended dose. Other NSAIDs not metabolized by CYP2C9 can be used at standard doses (e.g., aspirin, ketorolac, naproxen, and sulindac).


In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Reference: Theken KN et al. Clin Pharmacol Ther. 2020 Aug;108(2):191-200. PMID: 32189324.

SLCO1B1 and Pitavastatin

To compare statin-associated musculoskeletal symptoms (SAMS) by statin intensities with doses for SLCO1B1 decreased and poor function to guide alternative statin selection, click here. For recommendations for patients on existing statin therapy, see footnote below table*

SLCO1B1 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

SLCO1B1 Increased Function

Increased SLCO1B1 transporter function.


Normal myopathy risk expected.

Initiate standard dosing.

SLCO1B1 Normal Function

Normal SLCO1B1 transporter function.


Normal myopathy risk expected.

Initiate standard dosing.

SLCO1B1 Decreased Function

Decreased SLCO1B1 transporter function.


Moderate risk of statin-induced myopathy with 20 mg.

High risk of statin-induced myopathy with 40-80 mg.

Initiate ≤ 2 mg, if dose > 2 mg is needed, consider an alternative statin associated with lower risk or combination therapy.

SLCO1B1 Poor Function

No SLCO1B1 transporter function.


High risk of statin-induced myopathy with 2-4 mg.

Initiate ≤ 1 mg, if dose > 1 mg is needed, consider an alternative statin associated with lower risk or combination therapy.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Reference: Cooper-DeHoff RM et al. Clin Pharmacol Ther. 2022 May;111(5):1007-1021. PMID: 35152405.

*Recommendations for patients on existing statin therapy:

For patients who are currently taking a statin with moderate risk of statin-induced myopathy, if the statin has been continued at a stable dose for 4 weeks without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than 4 weeks clinicians can consider changing the statin or dose to a regimen with lower risk that meets the appropriate guideline recommended intensity.

For patients who are currently taking a statin with high risk of statin-induced myopathy, if the statin has been continued at a stable dose for at least 1 year without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than one year clinicians can consider changing the statin or dose to regimen with lower risk that meets the appropriate guideline recommended intensity.

To see statins with moderate and high risk of statin-induced myopathy, click here.

SLCO1B1 and Pravastatin

To compare statin-associated musculoskeletal symptoms (SAMS) by statin intensities with doses for SLCO1B1 decreased and poor function to guide alternative statin selection, click here. For recommendations for patients on existing statin therapy, see footnote below table*

SLCO1B1 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

SLCO1B1 Increased Function

Increased SLCO1B1 transporter function.


Normal myopathy risk expected.

Initiate standard dosing.

SLCO1B1 Normal Function

Normal SLCO1B1 transporter function.


Normal myopathy risk expected.

Initiate standard dosing.

SLCO1B1 Decreased Function

Decreased SLCO1B1 transporter function.


Moderate risk of statin-induced myopathy with 80 mg.

Initiate standard dosing.

SLCO1B1 Poor Function

No SLCO1B1 transporter function.

 
Moderate risk of statin-induced myopathy with 80 mg.

Initiate ≤ 40 mg, if dose >40 mg is needed, consider an alternative statin associated with lower risk or combination therapy.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Reference: Cooper-DeHoff RM et al. Clin Pharmacol Ther. 2022 May;111(5):1007-1021. PMID: 35152405.

*Recommendations for patients on existing statin therapy:

For patients who are currently taking a statin with moderate risk of statin-induced myopathy, if the statin has been continued at a stable dose for 4 weeks without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than 4 weeks clinicians can consider changing the statin or dose to a regimen with lower risk that meets the appropriate guideline recommended intensity.

For patients who are currently taking a statin with high risk of statin-induced myopathy, if the statin has been continued at a stable dose for at least 1 year without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than one year clinicians can consider changing the statin or dose to regimen with lower risk that meets the appropriate guideline recommended intensity.

To see statins with moderate and high risk of statin-induced myopathy, click here.

SLCO1B1, ABCG2 and Rosuvastatin

To compare statin-associated musculoskeletal symptoms (SAMS) by statin intensities with doses for SLCO1B1 decreased and poor function to guide alternative statin selection, click here. For recommendations for patients on existing statin therapy, see footnote below table*

If either SLCO1B1 or ABCG2 genotypes are unavailable, scroll down in this table to the “Instructions for Unavailable Genotypes”.

Predicted Phenotype

ABCG2 Normal Function


Normal ABCG2 transporter function.

 
Normal response expected based on ABCG2 alone.

ABCG2 Decreased Function


Decreased ABCG2 transporter function.

 
Increased chance for treatment success (i.e., lipid-lowering) based on ABCG2 alone.

ABCG2 Poor Function


Little ABCG2 transporter function.

 
Increased chance for treatment success (i.e., lipid-lowering) and potential risk for myopathy secondary to increased drug exposure based on ABCG2 alone.

SLCO1B1 Increased Function


Increased SLCO1B1 transporter function.

 
Normal myopathy risk expected based on SLCO1B1 alone.

Initiate standard dosing.

Initiate standard dosing.

Initiate ≤ 20 mg, if dose > 20 mg is needed, consider alternative statin or combination therapy.

SLCO1B1 Normal Function


Normal SLCO1B1 transporter function.

 
Normal myopathy risk expected based on SLCO1B1 alone.

Initiate standard dosing.

Initiate standard dosing.

Initiate ≤ 20 mg, if dose > 20 mg is needed, consider alternative statin or combination therapy.

SLCO1B1 Decreased Function


Decreased SLCO1B1 transporter function.

 
Moderate risk of statin-induced myopathy with 40 mg based on SLCO1B1 alone.

Initiate standard dosing.

Initiate standard dosing.

Initiate ≤ 10 mg, if dose > 10 mg is needed, consider alternative statin or combination therapy.

SLCO1B1 Poor Function


No SLCO1B1 transporter function.

 
High risk of statin-induced myopathy with 40 mg based on SLCO1B1 alone.

Initiate ≤ 20 mg, if dose > 20 mg is needed, consider combination therapy.

Initiate ≤ 20 mg, if dose > 20 mg is needed, consider combination therapy.

Initiate ≤ 10 mg, if dose > 10 mg is needed, consider combination therapy.

Instructions for Unavailable Genotypes

If for SLCO1B1 either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or SLCO1B1 was not genotyped, but ABCG2 is available, follow across the SLCO1B1 Normal Metabolizer row to the appropriate ABCG2 phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable SLCO1B1 genotype; consider testing or repeat testing of SLCO1B1 as appropriate.

 
If for ABCG2 either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or ABCG2 was not genotyped, but SLCO1B1 is available, follow down the ABCG2 Normal Metabolizer column to the appropriate SLCO1B1 phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable ABCG2 genotype; consider testing or repeat testing of ABCG2 as appropriate.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Resources

Reference: Cooper-DeHoff RM et al. Clin Pharmacol Ther. 2022 May;111(5):1007-1021. PMID: 35152405.

*Recommendations for patients on existing statin therapy:

For patients who are currently taking a statin with moderate risk of statin-induced myopathy, if the statin has been continued at a stable dose for 4 weeks without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than 4 weeks clinicians can consider changing the statin or dose to a regimen with lower risk that meets the appropriate guideline recommended intensity.

For patients who are currently taking a statin with high risk of statin-induced myopathy, if the statin has been continued at a stable dose for at least 1 year without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than one year clinicians can consider changing the statin or dose to regimen with lower risk that meets the appropriate guideline recommended intensity.

To see statins with moderate and high risk of statin-induced myopathy, click here.

SLCO1B1 and Simvastatin

To compare statin-associated musculoskeletal symptoms (SAMS) by statin intensities with doses for SLCO1B1 decreased and poor function to guide alternative statin selection, click here. For recommendations for patients on existing statin therapy, see footnote below table*

SLCO1B1 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

SLCO1B1 Increased Function

Increased SLCO1B1 transporter function.


Normal myopathy risk expected.

Initiate standard dosing.

SLCO1B1 Normal Function

Normal SLCO1B1 transporter function.


Normal myopathy risk expected.

Initiate standard dosing.

SLCO1B1 Decreased Function

Decreased SLCO1B1 transporter function.


Moderate risk of statin-induced myopathy with 10 mg.

High risk of statin-induced myopathy with 20-40 mg.

Consider an alternative statin associated with lower risk, if simvastatin is warranted, limit dose to < 20 mg/day.

SLCO1B1 Poor Function

No SLCO1B1 transporter function.

 
High risk of statin-induced myopathy with 10-40 mg.

Consider an alternative statin associated with lower risk.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Reference: Cooper-DeHoff RM et al. Clin Pharmacol Ther. 2022 May;111(5):1007-1021. PMID: 35152405.

*Recommendations for patients on existing statin therapy:

For patients who are currently taking a statin with moderate risk of statin-induced myopathy, if the statin has been continued at a stable dose for 4 weeks without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than 4 weeks clinicians can consider changing the statin or dose to a regimen with lower risk that meets the appropriate guideline recommended intensity.

For patients who are currently taking a statin with high risk of statin-induced myopathy, if the statin has been continued at a stable dose for at least 1 year without symptoms suggestive of statin-induced myopathy it may be reasonable to continue the current statin therapy, while if dosing has continued for less than one year clinicians can consider changing the statin or dose to regimen with lower risk that meets the appropriate guideline recommended intensity.

To see statins with moderate and high risk of statin-induced myopathy, click here.

CYP3A5 and Tacrolimus

These recommendations include the use of tacrolimus in kidney, heart, lung, and hematopoietic stem cell transplant patients, and liver transplant patients in which the donor and recipient genotypes are identical.

CYP3A5 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

Normal Metabolizer (CYP3A5 Expresser)

Functional CYP3A5 enzyme activity present (“Abnormal result”; inconsistent with the majority of the population).

 
Increased risk of treatment failure with standard doses.

Increase starting dose by 1.5–2 times the

recommended starting dose without exceeding
0.3 mg/kg/day. Adjust as clinically appropriate per therapeutic drug monitoring.

Intermediate Metabolizer
(CYP3A5 Expresser)

Functional CYP3A5 enzyme activity present (“Abnormal result”; inconsistent with the majority of the population).

 
Increased risk of treatment failure with standard doses.

Increase starting dose by 1.5–2 times the

recommended starting dose without exceeding

0.3 mg/kg/day. Adjust as clinically appropriate per therapeutic drug monitoring

Poor Metabolizer (CYP3A5 Non-Expresser)

No CYP3A5 enzyme activity (“Normal result”; consistent with the majority of the population).

 
Normal response expected.

Initiate standard dosing and adjust as clinically appropriate per therapeutic drug monitoring.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Reference: Birdwell KA et al. Clin Pharmacol Ther. 2015 Jul;98(1):19-24. PMID: 25801146.

CYP2D6 and Tamoxifen

Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the table below.

CYP2D6 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

Ultra Rapid Metabolizer
(Activity Score >2)

Increased CYP2D6 enzyme activity.

 
Normal response expected.

Use standard dose of tamoxifen.

Normal – Ultra Rapid Metabolizer with an enzyme Activity Score of 1.5+ or 2+*

Normal to increased CYP2D6 enzyme activity.

 
Normal response expected.

Use standard dose of tamoxifen.

Normal – Ultra Rapid Metabolizer with an enzyme Activity Score of 1+*

Normal to increased CYP2D6 enzyme activity.


Possibly reduced activation of tamoxifen and increased risk of treatment failure (e.g., high risk of breast cancer reoccurrence) or normal activation with normal response.

Consider alternative: aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression if premenopausal. If aromatase inhibitor is contraindicated, consider a higher dose (i.e., tamoxifen 40 mg/day).

Normal Metabolizer
with an enzyme Activity Score of 1.5 – 2.0*

Normal CYP2D6 enzyme activity.

 
Normal response expected.

Use standard dose of tamoxifen.

Normal Metabolizer
with an enzyme Activity Score of 1.0*

Normal CYP2D6 enzyme activity. 


Reduced activtion of tamoxifen and increased risk of treatment failure (e.g., high risk of breast cancer reocurrance). 

Consider alternative: aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression if premenopausal.  If aromatase inhibitor is contraindicated, consider a higher dose (i.e., tamoxifen 40 mg/day).

Intermediate Metabolizer
(Activity Score 0.25 – 0.75)*

Decreased CYP2D6 enzyme activity.

 
Reduced activation of tamoxifen and increased risk of treatment failure (e.g., high risk of breast cancer reoccurrence).

Consider alternative: aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression if premenopausal.  If aromatase inhibitor is contraindicated, consider a higher dose (i.e., tamoxifen 40 mg/day).

Poor Metabolizer
(Activity Score 0)

No CYP2D6 enzyme activity.


Significantly reduced activation of tamoxifen and increased risk of treatment failure (e.g., high risk
 of breast cancer reoccurrence).

Use alternative: aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression if premenopausal.

May consider higher dose of tamoxifen (40 mg/day) if contraindications to aromatase inhibitor exist, noting that activation of tamoxifen will increase but not normalize.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Reference: Goetz MP et al. Clin Pharmacol Ther. 2018 May;103(5):770-777. PMID: 29385237.

*Some laboratories have started calling activity scores of 1.0 as Intermediate Metabolizers, however they are still classified as Normal Metabolizers with UF Health Pathology.

TPMT, NUDT15 and Thioguanine

If either TPMT or NUDT15 genotypes are unavailable, scroll down in this table to the “Instructions for Unavailable Genotypes”.

TPMT Normal Metabolizer


Normal TPMT enzyme activity.

 
Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on TPMT alone.

TPMT Intermediate Metabolizer


Decreased TPMT enzyme activity.

 
Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on TPMT alone.

TPMT Poor – Intermediate Metabolizer


Decreased to no TPMT enzyme activity.

 
Increased to greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on TPMT alone.

TPMT Poor Metabolizer


No TPMT enzyme activity.

 
Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on TPMT alone.

NUDT15 Normal Metabolizer


Normal NUDT15 enzyme activity.

 
Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on NUDT15 alone.

Start with normal starting dose per disease-specific guidelines. Allow 2 weeks to reach steady-state after each dose adjustment.

Reduce starting doses by 50–80%. Allow 2–4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

NUDT15 Intermediate Metabolizer


Decreased NUDT15 enzyme activity.

 
Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on NUDT15 alone.

Reduce starting doses by 50–80%. Allow 2–4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents.

Reduce starting doses by 50–80%. Allow 2–4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents.

 
Due to the additive effect of both genes may require further dose reduction.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents.


For nonmalignant conditions:

Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

NUDT15 Poor – Intermediate Metabolizer


Decreased to no NUDT15 enzyme activity.

 
Increased to greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on NUDT15 alone.

For malignant conditions: Reduce starting dose by 75%. Allow 4–6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents.


For nonmalignant conditions:

Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Reduce starting dose by 75%. Allow 4–6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents.


For nonmalignant conditions:

Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

NUDT15 Poor Metabolizer


No NUDT15 enzyme activity.

 
Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression based on NUDT15 alone.

For malignant conditions: Reduce starting dose by 75%. Allow 4–6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Reduce starting dose by 75%. Allow 4–6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

For malignant conditions: Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily). Allow 4–6 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents.


For nonmalignant conditions:
Consider alternative nonthiopurine immunosuppressant therapy.

Instructions for Unavailable Genotypes

If for NUDT15 either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or NUDT15 was not genotyped, but TPMT is available, follow across the NUDT15 Normal Metabolizer row to the appropriate TPMT phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable NUDT15 genotype; consider testing or repeat testing of NUDT15 as appropriate.

 
If for TPMT either Assay Failure, Unable to Genotype, or Unknown Phenotype are resulted or TPMT was not genotyped, but NUDT15 is available, follow down the TPMT Normal Metabolizer column to the appropriate NUDT15 phenotype for the recommendation. These recommendations may be affected by the patient’s unavailable TPMT genotype; consider testing or repeat testing of TPMT as appropriate.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Resources

Reference: Relling MV et al. Clin Pharmacol Ther. 2019 May;105(5):1095-1105. PMID: 30447069.

CYP2D6 and Vortioxetine

Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the table below.

CYP2D6 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

Ultra Rapid Metabolizer

Increased CYP2D6 enzyme activity.

 
 Limited data available; possible increased risk of treatment failure.

Given limited data available, consider initiating therapy with recommended starting dose with careful monitoring.

Normal – Ultra Rapid Metabolizer*

Normal to increased CYP2D6 enzyme activity.

 
Limited data available; possible increased risk of treatment failure.

Given limited data available, consider initiating therapy with recommended starting dose with careful monitoring.

Normal Metabolizer*

Normal CYP2D6 enzyme activity.

 
Expected response.

Initiate therapy with recommended starting dose.

Intermediate Metabolizer*

Decreased CYP2D6 enzyme activity.

 
Limited data available.

Initiate therapy with recommended starting dose.

Poor Metabolizer

No CYP2D6 enzyme activity.

 
Increased risk of adverse effects (e.g., dizziness, GI dysfunction, sexual dysfunction).

Initiate vortioxetine at 5 mg once daily or consider an alternative drug (click here for table of alternatives). The maximum recommend dose of vortioxetine is 10 mg/day.  

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

*Some laboratories have started calling activity scores of 1.0 as Intermediate Metabolizers, however they are still classified as Normal Metabolizers with UF Health Pathology.

CYP2C9, VKORC1, rs12777823 (CYP2C Cluster) and Warfarin

Genotype information can be utilized along with clinical information to guide initial warfarin dosing and predict a patient’s stable daily warfarin dose. Utilize the flowchart below to determine which warfarin algorithm should be used and additional modifications warranted.*

Adults

Pediatric

*Note: This flow chart has been adapted from CPIC guidelines to reflect a pharmacogenetics panel that includes CYP2C9 *2,*3,*5,*6,*8,*11, VKORC1 1639G>A, and rs12777823(CYP2C Cluster). If you have results that include different variants, please follow the link to the CPIC guideline below to utilize the full flowchart.

Reference: Johnson JA et al. Clin Pharmacol Ther. 2017 Sep;102(3):397-404. PMID: 28198005.

Resources:
Warfarin Dosing CPIC Guideline
More Information on Warfarin Dosing from PharmGKB

CYP2C19 and Voriconazole

For the TREATMENT of invasive fungal infections:

CYP2C19 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

Ultra Rapid Metabolizer

Increased CYP2C19 enzyme activity.

 
Increased risk of subtherapeutic concentrations and treatment failure.

Choose an alternative agent that is
not dependent on CYP2C19 metabolism (e.g., isavuconazole, liposomal amphotericin B, and posaconazole).

Rapid Metabolizer

Increased CYP2C19 enzyme activity.

 
Increased risk of subtherapeutic concentrations and treatment failure.

Choose an alternative agent that is

not dependent on CYP2C19 metabolism (e.g., isavuconazole, liposomal amphotericin B, and posaconazole).

 
For pediatric patients:  Alternatively may be acceptable to initiate standard dosing with therapeutic drug monitoring, however it may be difficult to obtain therapeutic levels in a timely manner.

Normal Metabolizer

Normal CYP2C19 enzyme activity.

 
Normal response expected.

Use standard dose of voriconazole.

Intermediate Metabolizer

Decreased CYP2C19 enzyme activity.

 
Higher dose-adjusted trough concentrations and potential for increased risk of adverse effects (e.g., hepatotoxicity, visual disturbances, visual hallucinations, and other neurologic disorders).

Use standard dose of voriconazole.

Poor Metabolizer

No CYP2C19 enzyme activity.

 
Increased risk of adverse effects (e.g., hepatotoxicity, visual disturbances, visual hallucinations, and other neurologic disorders).

Choose alternative agent that is not dependent on CYP2C19 metabolism (e.g., isavuconazole, liposomal amphotericin B, and posaconazole).

 
If voriconazole is warranted, administer lower doses with therapeutic drug monitoring.

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

Reference: Moriyama B et al. Clin Pharmacol Ther. 2017 Jul;102(1):45-51. PMID: 27981572.

CYP2D6 and Venlafaxine

Strong and moderate inhibitors of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, terbinafine, cinacalcet, duloxetine, mirabegron, abiraterone, and lorcaserin) can lead to phenoconversion. If a patient is taking one or more of the above listed medications (and that medication will not be discontinued prior to starting the new medication of interest), use the CYP2D6 Phenoconversion Calculator to determine the clinical phenotype and use that phenotype in the table below.

CYP2D6 Predicted Phenotype

Clinical Implication

Therapeutic Recommendation

Resources

Ultra Rapid Metabolizer

Increased CYP2D6 enzyme activity.

 
Limited data available.

Initiate therapy with recommended starting dose.

Normal – Ultra Rapid Metabolizer*

Normal to increased CYP2D6 enzyme activity.

 
Limited data available.

Initiate therapy with recommended starting dose.

Normal Metabolizer*

Normal CYP2D6 enzyme activity.

 
Normal response expected.

Initiate therapy with recommended starting dose.

Intermediate Metabolizer*

Decreased CYP2D6 enzyme activity.

 
Limited data available.

Initiate therapy with recommended starting dose.

Poor Metabolizer

No CYP2D6 enzyme activity.

 
Increased risk of adverse effects (e.g., insomnia, GI dysfunction, sexual dysfunction, hyperhidrosis, increased blood pressure and heart rate) and possibly treatment failure.

Avoid venlafaxine and consider an alternative drug (click here for table of alternatives).

Unable to Genotype or Assay Failure

The analysis failed to yield an informative result and thus no genotype is reported.

Unknown Phenotype

This individual is carrying at least one allele with uncertain/unknown function and the predicted phenotype cannot be determined at this time.

*Some laboratories have started calling activity scores of 1.0 as Intermediate Metabolizers, however they are still classified as Normal Metabolizers with UF Health Pathology.

SLCO1B1 and Statin Selection Recommendations

The figure below provides statin specific statin-associated musculoskeletal symptoms (SAMS) risk, also known as statin-induced myopathy risk, based on SLCO1B1 predicted phenotype and statin intensity.

Recommendations for new start or dose changes in statin therapy:

This figure is for starting, changing dose, or selecting alternative statin therapy, for more specific recommendations see each individual statin table below, especially for fluvastatin and rosuvastatin, which utilize additional pharmacogenetic information.

Recommendations for patients on existing statin therapy:

For patients on existing moderate SAMS risk statin therapy, if the statin has been continued at a stable dose for 4 weeks without symptoms suggestive of SAMS it may be reasonable to continue the moderate SAMS risk statin therapy, while if dosing has continued for less than 4 weeks clinicians can consider changing the statin or dose to a low SAMS risk regimen that meets the appropriate guideline recommended intensity.

For patients on existing high SAMS risk statin therapy, if the statin has been continued at a stable dose for at least 1 year without symptoms suggestive of SAMS it may be reasonable to continue the high SAMS risk statin therapy, while if dosing has continued for less than one year clinicians can consider changing the statin or dose to a low SAMS risk regimen that meets the appropriate guideline recommended intensity.

SLCO1B1 and Statin Selection Recommendations

Reference: Cooper-DeHoff RM et al. Clin Pharmacol Ther. 2022 May;111(5):1007-1021. PMID: 35152405.

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