Annotation of CPIC Guideline for atomoxetine and CYP2D6

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Dosing InfoPediatric

Summary

The CPIC Dosing Guideline for atomoxetine provides therapeutic recommendations for CYP2D6 ultrarapid, normal, intermediate, and poor metabolizer, which includes guidance for plasma drug concentration testing, as a means to estimate atomoxetine exposure, if no clinical response and in the absence of adverse events after 2 weeks of therapy.

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Annotation

This annotation is based on the CPIC® guideline for atomoxetine and CYP2D6.

October 2019 Update

CYP2D6 genotype to phenotype translation changes: Up until August 2019, there were a few inconsistencies in the translation of CYP2D6 genotype to phenotype translation across guidelines (i.e. CPIC and DPWG) and between clinical genetic testing laboratories. CPIC recently conducted a modified-Delphi project to obtain consensus for a uniform system for translating CYP2D6 genotype to phenotype among a panel of international CYP2D6 experts more information. Modifications to CPIC’s prior system include downgrading the value assigned to the CYP2D6*10 allele for activity score calculation from 0.5 to 0.25 and changing the phenotype assignment for an activity score of 1 from normal metabolizer to intermediate metabolizer (table of all previous and new phenotype groupings).

As a result, the following changes have been made in the CYP2D6 allele functionality table, CYP2D6 genotype to phenotype table, Atomoxetine pre- and post-test alerts and flow chart (access tables below):

Activity scores of 1 changed from CYP2D6 normal metabolizer to CYP2D6 intermediate metabolizer.
- Impact on the recommendations in this guideline: The current guideline has a specific recommendation for AS of 1 (no CYP2D6*10 allele present); thus, the current published recommendations for normal and intermediate metabolizer will remain unchanged.
All activity scores for diplotypes containing a CYP2D6*10 allele have been updated accordingly (activity scores changed to reflect the lower activity value of 0.25 for CYP2D6*10). See table of all previous and new phenotype groupings.
- Impact on the recommendations in this guideline: The recommendations for ultrarapid and normal metabolizers are the same so this change does not impact the recommended prescribing recommendations. The recommendations for the activity score of 1 (with a CYP2D6*10 allele present) and 0.5 are the same so the current published recommendations for this diplotype will remain unchanged.

February 2018

Advance online publication February 2019

The CPIC guidelines regarding the use of pharmacogenomic tests in dosing of atomoxetine have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).
These guidelines are applicable to:
- pediatric patients
- adult patients
Excerpts from the 2019 dosing guideline:
- "CYP2D6 genetic variation has a profound effect on atomoxetine pharmacokinetics. .... Atomoxetine exposure (AUC) is, on average, 10-fold higher in CYP2D6 PMs compared to non-PMs. .... Individuals with two CYP2D6*10 alleles had higher atomoxetine exposure (5-fold higher peak concentration) when compared to individuals with at least one normal function allele."
- "The most well studied pharmacokinetic parameter for atomoxetine relates plasma drug concentrations that approximate the Cmax of the parent compound to reduction of ADHD symptoms. Given this evidence, the therapeutic recommendation for each CYP2D6 phenotype class also includes guidance for plasma drug concentration testing, as a means to estimate atomoxetine exposure (i.e. exposure check). These target reference values are from the Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology [Article:29493375], and are meant to guide the clinician in the event that patient response to atomoxetine is inadequate."
- "Data from both in vitro and in vivo studies (supplemental table 1), as well as consensus recommendations were used in formulating the guidance."
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Table 1: Recommended dosing of atomoxetine by CYP2D6 genotype/phenotype for children.

Adapted from Tables 1 and 2 of the 2019 guideline manuscript.

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Phenotype^a	Activity Score	Genotype	Examples of genotypes^b	Implications	Therapeutic recommendations	Classification of recommendations^c
CYP2D6 Ultrarapid Metabolizer	>2	An individual carrying duplications of functional alleles	1/1xN, 1/2xN, 2/2xN^d	Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing.	Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/ml, consider a proportional increase in dose to approach 400 ng/ml.^e,f	Moderate
CYP2D6 Normal metabolizer	1.5 and 2	An individual carrying two normal function alleles or one normal function and one decreased function allele	1/1, 1/2, 1/9, 1/41, 2/2	Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers.	Initiate with a dose of 0.5 mg/kg and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/ml, consider a proportional increase in dose to approach 400 ng/ml.^e,f	Moderate
CYP2D6 Normal metabolizer or Intermediate metabolizer (controversy remains)^g	1 (no *10 allele present)^h	An individual carrying two decreased function alleles or one normal function and one no function allele. An activity score (AS) of 1.0 is associated with decreased atomoxetine metabolism compared to those with an AS of 1.5 or 2.	1/4, 1/5, 41/41	Possibly higher atomoxetine concentrations as compared to normal metabolizers but questionable clinical significance. Normal metabolizers may be at an increased risk of increased discontinuation as compared to poor metabolizers.	Initiate with a dose of 0.5 mg/kg and increase to 1.2 mg/kg/day after 3 days If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/ml, consider a proportional increase in dose to approach 400 ng/ml.^e,f	Moderate
CYP2D6 Normal metabolizer or Intermediate metabolizer (controversy remains)^g	1 (*10 allele present)^h	An individual carrying two decreased function alleles or one normal function and one no function allele. An activity score (AS) of 1.0 is associated with decreased atomoxetine metabolism compared to those with an AS of 1.5 or 2.	10/10, 10/41	Decreased metabolism of atomoxetine and higher atomoxetine concentrations as compared to normal metabolizers. Individuals with activity score of 1.0 with CYP2D6*10 may be at an increased risk of increased discontinuation as compared to poor metabolizers.	Initiate with a dose of 0.5 mg/kg/day and if no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a plasma concentration 2-4 h after dosing. If response is inadequate and concentration is <200 ng/ml, consider a proportional dose increase to achieve a concentration to approach 400 ng/ml.^e,f If unacceptable side effects are present at any time, consider a reduction in dose.	Moderate
CYP2D6 Intermediate metabolizer	0.5	An individual carrying one decreased function and one no function allele	4/10,4/41, 5/9	Decreased metabolism of atomoxetine and higher atomoxetine concentrations as compared to normal metabolizers. Intermediate metabolizers may be at an increased risk of discontinuation as compared to poor metabolizers.	Initiate with a dose of 0.5 mg/kg/day and if no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a plasma concentration 2-4 h after dosing. If response is inadequate and concentration is <200 ng/ml, consider a proportional dose increase to achieve a concentration to approach 400 ng/ml.^e,f If unacceptable side effects are present at any time, consider a reduction in dose.	Moderate
CYP2D6 Poor metabolizer	0	An individual carrying only no functional alleles	3/4,4/4, 5/5, 5/6	Significantly decreased metabolism of atomoxetine may result in higher concentrations as compared to non-poor metabolizers. This may increase the occurrence of treatment-emergent side effects, but also a greater improvement of ADHD symptoms as compared to non-poor metabolizers in those who tolerate treatment. Poor metabolizer status is associated with lower final dose requirements as compared to non-poor metabolizers.	Initiate with a dose of 0.5 mg/kg/day and if no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a plasma concentration 4 h after dosing. If response is inadequate and concentration is <200 ng/ml, consider a proportional dose increase to achieve a concentration to approach 400 ng/ml.^e,f If unacceptable side effects are present at any time, consider a reduction in dose.	Strong

^a See the CYP2D6 Frequency Table for race-specific allele and phenotype frequencies CYP2D6 tables.
^b Assignment of allele function and citations for allele function can be found in the CYP2D6 Allele Definition Table and CYP2D6 Allele Functionality Table. For a complete list of CYP2D6 diplotypes and resulting phenotypes, see the CYP2D6 Genotype to Phenotype Table CYP2D6 tables. Note that genotypes with an activity score of 1 are classified as NMs in the online CYP2D6 genotype to phenotype table.
^c Rating scheme described in Supplement.
^d Where xN represents the number of CYP2D6 gene copies. For individuals with CYP2D6 duplications or multiplications, see supplemental data for additional information on how to translate diplotypes into phenotypes.
^e Therapeutic range of 200 to 1000 ng/ml has been proposed [Article:29493375].
^f Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in PMs compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-RS, is observed at peak concentrations greater than 400 ng/ml.
^g Patients with an activity score of 1.0 may be classified as intermediate metabolizers by some reference laboratories. A group of CYP2D6 experts are currently working to standardize the CYP2D6 genotype to phenotype translation system. CPIC will update the CPIC website accordingly.
^h CPIC has general classified patients with activity score of 1 as “normal metabolizer.” However, in the case of atomoxetine, prescribing recommendations for those with an AS of 1.0 are allele-dependent, based on the presence of the CYP2D6*10 allele.

Table 2: Recommended dosing of atomoxetine by CYP2D6 genotype/phenotype for adults.

Adapted from Tables 1 and 3 of the 2019 guideline manuscript.

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Phenotype^a	Activity Score	Genotype	Examples of genotypes^b	Implications	Therapeutic recommendations	Classification of recommendations^c
CYP2D6 Ultrarapid Metabolizer	>2	An individual carrying duplications of functional alleles	1/1xN, 1/2xN, 2/2xN^d	Based on very limited data available for CYP2D6 ultrarapid metabolizers taking atomoxetine, it is unlikely ultrarapid metabolizers would achieve adequate serum concentrations for the intended effect at standard dosing.	Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/ml, consider a proportional increase in dose to approach 400 ng/ml.^e,f Dosages greater than 100 mg/day may be needed to achieve target concentrations.^g	Moderate
CYP2D6 Normal metabolizer	1.5 and 2	An individual carrying two normal function alleles or one normal function and one decreased function allele	1/1, 1/2, 1/9, 1/41, 2/2	Normal metabolizers of atomoxetine have a lower likelihood of response as compared to poor metabolizers. This is associated with increased discontinuation due to lack of efficacy as compared to poor metabolizers.	Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/ml, consider a proportional increase in dose to approach 400 ng/ml.^e,f Dosages greater than 100 mg/day may be needed to achieve target concentrations.^g	Moderate
CYP2D6 Normal metabolizer or Intermediate metabolizer (controversy remains)^h	1 (no *10 allele present)ⁱ	An individual carrying two decreased function alleles or one normal function and one no function allele. An activity score (AS) of 1.0 is associated with decreased atomoxetine metabolism compared to those with an AS of 1.5 or 2.	1/4, 1/5, 41/41	Possibly higher atomoxetine concentrations as compared to normal metabolizers but questionable clinical significance. Normal metabolizers may be at an increased risk of increased discontinuation as compared to poor metabolizers.	Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 to 2 hours after dose administered). If <200 ng/ml, consider a proportional increase in dose to approach 400 ng/ml.^e,f Dosages greater than 100 mg/day may be needed to achieve target concentrations.^g	Moderate
CYP2D6 Normal metabolizer or Intermediate metabolizer (controversy remains)^h	1 (*10 allele present)ⁱ	An individual carrying two decreased function alleles or one normal function and one no function allele. An activity score (AS) of 1.0 is associated with decreased atomoxetine metabolism compared to those with an AS of 1.5 or 2.	10/10, 10/41	Decreased metabolism of atomoxetine and higher atomoxetine concentrations as compared to normal metabolizers. Individuals with activity score of 1.0 with CYP2D6*10 may be at an increased risk of increased discontinuation as compared to poor metabolizers.	Initiate with a dose of 40 mg/day and if no clinical response and in the absence of adverse events after 2 weeks increase dose to 80 mg/day. If response is inadequate after 2 weeks consider obtaining a plasma concentration 2-4 h after dosing. If concentration is <200 ng/ml, consider a proportional dose increase to achieve a concentration to approach 400 ng/ml.^e,f If unacceptable side effects are present at any time, consider a reduction in dose.	Moderate
CYP2D6 Intermediate metabolizer	0.5	An individual carrying one decreased function and one no function allele	4/10,4/41, 5/9	Decreased metabolism of atomoxetine and higher atomoxetine concentrations as compared to normal metabolizers. Intermediate metabolizers may be at an increased risk of discontinuation as compared to poor metabolizers.	Initiate with a dose of 40 mg/day and if no clinical response and in the absence of adverse events after 2 weeks increase dose to 80 mg/day. If response is inadequate after 2 weeks consider obtaining a plasma concentration 2-4 h after dosing. If concentration is <200 ng/ml, consider a proportional dose increase to achieve a concentration to approach 400 ng/ml.^e,f If unacceptable side effects are present at any time, consider a reduction in dose.	Moderate
CYP2D6 Poor metabolizer	0	An individual carrying only no functional alleles	3/4,4/4, 5/5, 5/6	Significantly decreased metabolism of atomoxetine may result in higher concentrations as compared to non-poor metabolizers. This may increase the occurrence of treatment-emergent side effects, but also a greater improvement of ADHD symptoms as compared to non-poor metabolizers in those who tolerate treatment. Poor metabolizer status is associated with lower final dose requirements as compared to non-poor metabolizers.	Initiate with a dose of 40 mg/day and if no clinical response and in the absence of adverse events after 2 weeks increase dose to 80 mg/day. If response is inadequate after 2 weeks consider obtaining a plasma concentration 2-4 h after dosing. If concentration is <200 ng/ml, consider a proportional dose increase to achieve a concentration to approach 400 ng/ml.^e,f If unacceptable side effects are present at any time, consider a reduction in dose.	Moderate

^a See the CYP2D6 Frequency Table for race-specific allele and phenotype frequencies CYP2D6 tables.
^b Assignment of allele function and citations for allele function can be found in the CYP2D6 Allele Definition Table and CYP2D6 Allele Functionality Table. For a complete list of CYP2D6 diplotypes and resulting phenotypes, see the CYP2D6 Genotype to Phenotype Table CYP2D6 tables. Note that genotypes with an activity score of 1 are classified as NMs in the online CYP2D6 genotype to phenotype table.
^c Rating scheme described in Supplement.
^d Where xN represents the number of CYP2D6 gene copies. For individuals with CYP2D6 duplications or multiplications, see supplemental data for additional information on how to translate diplotypes into phenotypes.
^e Therapeutic range of 200 to 1000 ng/ml has been proposed [Article:29493375].
^f Limited data are available regarding the relationship between atomoxetine plasma concentrations and clinical response. Available information suggests that clinical response is greater in PMs compared to non-PMs and may be related to the higher plasma concentrations 1 to 1.5 hours after dosing in PMs compared to non-PMs administered a similar dose. Furthermore, modest improvement in response, defined as reduction in ADHD-RS, is observed at peak concentrations greater than 400 ng/ml.
^g Doses above 120 mg/day have not been evaluated.
^h Patients with an activity score of 1.0 may be classified as intermediate metabolizers by some reference laboratories. A group of CYP2D6 experts are currently working to standardize the CYP2D6 genotype to phenotype translation system. CPIC will update the CPIC website accordingly.
ⁱ CPIC has general classified patients with activity score of 1 as “normal metabolizer.” However, in the case of atomoxetine, prescribing recommendations for those with an AS of 1.0 are allele-dependent, based on the presence of the CYP2D6*10 allele.

PharmGKB ID

PA166181885