Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors

Abstract

Selective Serotonin Reuptake Inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org).

Introduction

Interindividual differences in pharmacokinetic parameter values and treatment outcomes with the Selective Serotonin Reuptake Inhibitors (SSRIs) are associated with CYP2D6 or CYP2C19 polymorphisms (1). The purpose of this guideline is to provide information to allow the interpretation of existing CYP2D6 and/or CYP2C19 genotype tests to guide SSRI dosing, particularly focusing on fluvoxamine, paroxetine, citalopram, escitalopram and sertraline. Other clinical variables that may influence SSRI therapy as well as genotyping cost-effectiveness are beyond the scope of this document. CPIC guidelines are periodically updated at http://www.pharmgkb.org.

Focused Literature Review

A systematic literature review focusing on CYP2D6 and CYP2C19 genotype and the influence on SSRI therapy was conducted (Supplemental Data).

Genes: CYP2D6 and CYP2C19

CYP2D6 Background

CYP2D6 is highly polymorphic with over 100 known allelic variants and subvariants identified (http://www.cypalleles.ki.se/cyp2d6.htm; Supplemental Table S1 and S2). CYP2D6 alleles have been extensively studied in multiple geographically, racially, and ethnically diverse groups and significant differences in allele frequencies have been observed (Supplemental Table S3). The most commonly reported alleles are categorized into functional groups as follows: Normal function (e.g., CYP2D6*1 and *2), decreased function (e.g., CYP2D6*9, *10, and *41), and no function (e.g., CYP2D6*3-*6) (2, 3). Because CYP2D6 is subject to deletions, gene duplications or multiplications, many clinical laboratories also report copy number variations. CYP2D6*5 represents a gene deletion whereas gene duplications and multiplications are denoted by “xN” (e.g. CYP2D6*1xN with xN representing the number of CYP2D6 gene copies).

CYP2C19 Background

Similar to CYP2D6, the CYP2C19 gene is highly polymorphic with significant differences in allele frequencies observed among populations. Over 30 allelic variants and subvariants have been identified (http://www.cypalleles.ki.se/cyp2c19.htm; Supplemental Tables S4 and S5); however, the majority of patients will carry CYP2C19*1,*2 or *17 alleles. CYP2C19*1 encodes a normal function enzyme, while CYP2C19*2 is the most common no function allele followed by CYP2C19*3. The CYP2C19*17 allele is defined by a variant in the promoter region resulting in enhanced gene transcription leading to increased metabolic capacity (4). Allele frequencies are provided in Supplemental Table S6.

Genetic Test Interpretation

Clinical laboratories usually test for the more frequently observed CYP2D6 and CYP2C19 genetic variants and translate the results into star-allele (*) nomenclature. Each star-allele, or haplotype, is defined by a specific combination of single-nucleotide polymorphisms and/or other genetic variants within the CYP2D6 or CYP2C19 gene locus (2, 5). Supplemental Tables S2 and S5 provide a list of CYP2D6 and CYP2C19 alleles and their functional status. Genetic test results are reported as the summary of inherited maternal and paternal star-alleles referred to as a diplotype (e.g., CYP2D6*1/*2 and CYP2C19*1/*1). Supplemental Data (Genetic Test Interpretation Section) contains additional information regarding CYP2D6 and CYP2C19 genetic test interpretation and phenotype assignment.

Different clinical laboratories may use varying methods to predict phenotype from genotype data. Therefore, before any pharmacotherapy modifications are made based upon this guideline, it is advisable to predict a patient's phenotype from genotype as described above and in the Supplemental Data.

Available Genetic Test Options

Information on commercially available clinical testing options can be found in the Supplemental Data, www.pharmgkb.org, or the Genetic Testing Registry (http://www.ncbi.nlm.nih.gov/gtr/).

Incidental Findings

Some studies have reported an association between CYP2D6 and CYP2C19 genetic variants and risk for depression or suicide (Supplemental Data). These associations are poorly understood and may be due to either alterations in endogenous physiology or drug metabolism. At present CYP2D6 and CYP2C19 are not considered to be clinically useful predictors of depression or suicide risk, nor have they been directly implicated in any Mendelian disorders.

Other Considerations

One of the limitations inherent in a genotype-only test is that rare or de novo variants will most likely not be included in any commercially available genotyping test. Other important considerations pertaining to genetic testing and genetic test interpretation are contained within the Supplemental Data.

Drugs: SSRIs

Background

SSRIs are a first line treatment option for major depressive and anxiety disorders, and may be used to treat other psychiatric conditions such as obsessive compulsive disorder. Although pharmacokinetic properties vary among this drug class, all of the SSRIs selectively increase serotonergic activity by decreasing presynaptic serotonin reuptake. The more common adverse effects induced by this drug class include central nervous system effects (e.g., insomnia, headache), gastrointestinal dysfunction, and sexual dysfunction; however, the incidence of side effect occurrence differs with each drug. Serious adverse events such as arrhythmias caused by QT prolongation have been associated with SSRIs, particularly for individuals prescribed citalopram who are CYP2C19 poor metabolizers (6).

Patients may be predisposed to poor therapeutic outcomes due to CYP2D6 or CYP2C19 polymorphisms that alter SSRI biotransformation. Paroxetine and fluvoxamine are extensively metabolized by CYP2D6 to compounds with little pharmacological activity towards serotonin reuptake inhibition (Supplemental Figure S1) (7, 8). Variations in CYP2D6 activity may result in lower or greater exposure to these drugs. Fluoxetine metabolism is more complex as both CYP2D6 and CYP2C9 convert fluoxetine to pharmacologically active norfluoxetine enantiomers (Supplemental Figure S1) (1).

Citalopram is a racemic mixture of R- and S-enantiomers, with the pharmacologically active S-enantiomer marketed as escitalopram. Citalopram and escitalopram are extensively metabolized by CYP2C19 to compounds that confer less serotonin reuptake inhibition (Supplemental Figure S1) (9). Sertraline is metabolized by CYP2D6, CYP2C19 and other polymorphic cytochrome P450 enzymes, with pharmacokinetic data suggesting that CYP2C19 is the major metabolic pathway (Supplemental Figure S1) (1). Because citalopram, escitalopram, and sertraline are extensively catalyzed by CYP2C19, variations in CYP2C19 activity may result in altered drug exposure.

Linking genetic variability to variability in drug-related phenotypes

For those diagnosed with major depressive disorder, approximately 50% will fail initial SSRI therapy (10). Furthermore, an estimated 25,000 patients per year in the United States will seek medical treatment in emergency departments due to adverse events associated with antidepressants (11). Utilizing existing pharmacogenetic results to guide SSRI therapy could potentially improve treatment response and decrease the occurrence of adverse events (12-14). There is substantial evidence linking CYP2D6 or CYP2C19 genotype to phenotypic variability in SSRI pharmacokinetic parameters or treatment outcomes (Supplemental Data). The application of a grading system to the evidence linking CYP2D6 and CYP2C19 genotypes to SSRI pharmacokinetic variability indicates a moderate to high quality of evidence for the majority of data (Supplemental Tables S7-S11). This body of evidence, rather than randomized clinical trials, provides the basis for SSRI pharmacotherapy recommendations in Tables 2 and 3.

Table 2. Dosing Recommendations for CYP2D6 and SSRIs.

a. Dosing Recommendation for Paroxetine based on CYP2D6 phenotype
Phenotype	Implication	Therapeutic Recommendation	Classification of Recommendationa
CYP2D6 Ultrarapid metabolizer	Increased metabolism to less active compounds when compared to extensive metabolizers. Lower/undetectable plasma concentrations may increase probability of pharmacotherapy failure.	Select alternative drug not predominantly metabolized by CYP2D6.b	Strong
CYP2D6 Extensive metabolizer	Normal metabolism	Initiate therapy with recommended starting dose.	Strong
CYP2D6 Intermediate metabolizer	Reduced metabolism when compared to extensive metabolizers. Higher plasma concentrations may increase the probability of side effects.	Initiate therapy with recommended starting dose.	Moderate
CYP2D6 Poor metabolizer	Greatly reduced metabolism when compared to extensive metabolizers. Higher plasma concentrations may increase the probability of side effects.	Select alternative drug not predominantly metabolized by CYP2D6b or if paroxetine use warranted, consider a 50% reduction of recommended starting dose and titrate to response.	Optional
b.Dosing Recommendation for Fluvoxamine based on CYP2D6 phenotype
CYP2D6 Ultrarapid metabolizer	No data available for CYP2D6 Ultrarapid Metabolizers.	No recommendation due to lack of evidence.c	Optional
CYP2D6 Extensive metabolizer	Normal metabolism	Initiate therapy with recommended starting dose.	Strong
CYP2D6 Intermediate metabolizer	Reduced metabolism when compared to extensive metabolizers. Higher plasma concentrations may increase the probability of side effects.	Initiate therapy with recommended starting dose.	Moderate
CYP2D6 Poor metabolizer	Greatly reduced metabolism when compared to extensive metabolizers. Higher plasma concentrations may increase the probability of side effects.	Consider a 25-50% reductiond of recommended starting dose and titrate to response or use an alternative drug not metabolized by CYP2D6.b	Optional

^aRating scheme described in Supplement.

^bDrug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

^cData are lacking describing the effect of CYP2D6 ultrarapid metabolism on fluvoxamine therapy; therefore no dosing recommendations are provided for fluvoxamine use for of CYP2D6 ultrarapid metabolizers. It may be reasonable, though, to select an alternative SSRI not extensively metabolized by CYP2D6 due to the lack of data describing how CYP2D6 ultrarapid metabolizer status influences fluvoxamine therapy.

^dDose extrapolations based on differences in pharmacokinetic parameters between phenotype groups suggest a 30% dose reduction of fluvoxamine (1). However, a 30% decrease in dose may not be feasible given the dosage forms, therefore, decreasing the starting dose of fluvoxamine by 25-50% should be considered.

Table 3. Dosing Recommendations for CYP2C19 and SSRIs.

a. Dosing Recommendations for Citalopram and Escitalopram based on CYP2C19 Phenotype
Phenotype	Implication	Therapeutic Recommendation	Classification of Recommendationa
CYP2C19 Ultrarapid metabolizer	Increased metabolism when compared to extensive metabolizers. Lower plasma concentrations will increase probability of pharmacotherapy failure.	Consider an alternative drug not predominantly metabolized by CYP2C19.b	Moderate
CYP2C19 Extensive metabolizer	Normal metabolism	Initiate therapy with recommended starting dose.	Strong
CYP2C19 Intermediate metabolizer	Reduced metabolism when compared to extensive metabolizers.	Initiate therapy with recommended starting dose.	Strong
CYP2C19 Poor metabolizer	Greatly reduced metabolism when compared to extensive metabolizers. Higher plasma concentrations may increase the probability of side effects.	Consider a 50% reductionc,d of recommended starting dose and titrate to response or select alternative drug not predominantly metabolized by CYP2C19.b	Moderate
b. Dosing Recommendations for Sertraline based on CYP2C19 Phenotype
Phenotype	Implication	Therapeutic Recommendation	Classification of Recommendationa
CYP2C19 Ultrarapid metabolizer	Increased metabolism when compared to extensive metabolizers.	Initiate therapy with recommended starting dose. If patient does not respond to recommended maintenance dosing, consider alternative drug not predominantly metabolized by CYP2C19.b	Optional
CYP2C19 Extensive metabolizer	Normal metabolism	Initiate therapy with recommended starting dose.	Strong
CYP2C19 Intermediate metabolizer	Reduced metabolism when compared to extensive metabolizers.	Initiate therapy with recommended starting dose.	Strong
CYP2C19 Poor metabolizer	Greatly reduced metabolism when compared to extensive metabolizers. Higher plasma concentrations may increase the probability of side effects.	Consider a 50% reductiond of recommended starting dose and titrate to response or select alternative drug not predominantly metabolized by CYP2C19.b	Optional

^aRating scheme described in Supplemental Materials.

^bDrug-drug interactions and other patient characteristics (e.g., age, renal function, liver function) should be considered when selecting an alternative therapy.

^cPer the FDA warning, citalopram 20 mg/day is the maximum recommended dose in CYP2C19 poor metabolizers due to the risk of QT prolongation. FDA product labeling additionally cautions that citalopram dose should be limited to 20 mg/day in patients with hepatic impairment, those taking a CYP2C19 inhibitor, and patients greater than 60 years of age.

^dPercent dose adjustments corresponding to percent difference in oral clearances have been calculated/estimated by Stingl et al. (1).

Therapeutic Recommendations

The recommendations below and in Tables 2 and 3 apply primarily to actions based on genetic tests only; drug interactions and other clinical factors can have a major influence for prescribing decisions for SSRIs and should be taken into consideration before initiating drug therapy. Based on the current literature, recommendations are made for paroxetine, fluvoxamine, citalopram, escitalopram, and sertraline. Considerations regarding fluoxetine are discussed below and can be found in the Supplemental Material.

CYP2D6-paroxetine and fluvoxamine dosing recommendations

Table 2 summarizes the dosing recommendations for paroxetine (Table 2a) and fluvoxamine (Table 2b) based on CYP2D6 phenotype. Multiple studies have demonstrated that CYP2D6 ultrarapid metabolizers have low or undetectable paroxetine plasma concentrations when compared to CYP2D6 extensive metabolizers (15-18). Those with undetectable paroxetine plasma concentrations are likely at risk of therapeutic failure. Low paroxetine plasma concentrations may be a risk factor for therapy failure, though the minimal paroxetine therapeutic concentration is not well defined (19). Because of the risk for therapy failure due to lower drug exposure, an alternative SSRI not extensively metabolized by CYP2D6 should be considered. There are insufficient data to calculate an initial paroxetine dose for CYP2D6 ultrarapid metabolizers. Data are lacking describing the effect of CYP2D6 ultrarapid metabolism on fluvoxamine therapy; therefore no dosing recommendations are provided for fluvoxamine in the context of CYP2D6 ultrarapid metabolizers. It may be reasonable, though, to select an alternative SSRI not extensively metabolized by CYP2D6 due to the lack of data describing how CYP2D6 ultrarapid metabolizer status influences fluvoxamine therapy.

Adjustments to paroxetine or fluvoxamine therapy are not warranted based on CYP2D6 status for those who are CYP2D6 extensive or intermediate metabolizers. Self-inhibition of CYP2D6, and potential phenoconversion may lead to non-linear kinetics at common doses in certain genotypes. Although CYP2D6 intermediate metabolizers may be expected to have a modest increase in drug exposure and may be more susceptible to CYP2D6 inhibition by paroxetine, existing evidence does not support paroxetine or fluvoxamine therapy adjustments. In addition, because CYP2D6 diplotypes are inconsistently categorized as extensive or intermediate metabolizers, the literature is difficult to evaluate, thus resulting in a moderate recommendation classification for intermediate metabolizers.

When administered similar doses, CYP2D6 poor metabolizers have significantly greater drug exposure to paroxetine and fluvoxamine when compared to extensive metabolizers (15, 20-22). This increase in drug exposure may be a risk factor for drug-induced side effects. The US Food and Drug Administration (FDA) states that fluvoxamine should be used cautiously inpatients known to have reduced levels of CYP2D6 activity (http://www.pharmgkb.org/label/PA166104854). To potentially prevent an adverse effect, an alternative SSRI not extensively metabolized by CYP2D6 should be considered for poor metabolizers. If paroxetine or fluvoxamine is warranted, dose extrapolations based on differences in pharmacokinetic parameters between phenotype groups suggest a 50% dose reduction of paroxetine and a 30% dose reduction of fluvoxamine (1). However, a 30% decrease in fluvoxamine dose may not be feasible given the dosage forms, therefore, decreasing the dose of fluvoxamine by 25-50% may help prevent adverse events by limiting high drug exposures. Because therapeutic drug monitoring is not common for SSRIs (19), limited data are available describing the linearity of the dose-concentration relationship and the relation between paroxetine or fluvoxamine concentrations and therapeutic effect and tolerability. Therefore, this recommendation is considered to be optional.

Fluoxetine considerations

CYP2D6 converts fluoxetine to S-norfluoxetine while both CYP2D6 and CYP2C9 convert fluoxetine to R-norfluoxetine (Supplemental Figure S1). Fluoxetine and R/S-norfluoxetine modulate serotonin reuptake, though R-norfluoxetine is thought be less pharmacologically active. CYP2D6 poor metabolizers have been demonstrated to possess significantly higher fluoxetine plasma concentrations than extensive metabolizers (Supplemental Table S10). However, the total sum of fluoxetine plus norfluoxetine plasma concentrations may not vary significantly by CYP2D6 phenotypes. Little data are available describing how CYP2D6 phenotype status influences the total sum of fluoxetine plus norfluoxetine concentrations over time, or if an imbalance between fluoxetine and norfluoxetine concentrations caused by CYP2D6 phenotype status affects patient outcome or safety. Therefore, no gene-based dosing recommendations are provided for fluoxetine. For CYP2D6 ultrarapid and poor metabolizers, it may be reasonable to monitor these patients more closely if they are prescribed fluoxetine or to select an alternative SSRI not extensively metabolized by CYP2D6 due to conflicting/inconclusive data describing how CYP2D6 status influences fluoxetine therapy. It is important to note that the prescribing information for fluoxetine states that the drug “should be used with caution in patients with congenital long QT syndrome” and that caution is warranted in situations that may prolong QT such as “conditions that predispose to increased fluoxetine exposure (overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 poor metabolizer status, or use of other highly protein-bound drugs).”

CYP2C19-citalopram, escitalopram and sertraline dosing recommendations

Table 3 summarizes the dosing recommendations for citalopram and escitalopram based on CYP2C19 phenotype. CYP2C19 ultrarapid metabolizers have significantly lower exposure to these drugs when compared to extensive metabolizers, and therefore may have an increased probability of failing therapy (9, 23, 24). Because there are insufficient data to calculate an initial citalopram or escitalopram dose for CYP2C19 ultrarapid metabolizers, an alternative SSRI not extensively metabolized by CYP2C19 may be an option if deemed appropriate given other medications and clinical considerations. Drug-drug interactions should be considered if selecting an alternative SSRI, such as paroxetine, which inhibits CYP2D6. CYP2C19*17 homozygotes have a greater metabolic capacity than CYP2C19*17 heterozygotes, and may benefit more from alternative therapy (23, 24). Given that there may be clinically significant differences among CYP2C19 ultrarapid metabolizers based on diplotype (i.e., CYP2C19*1/*17 versus CYP2C19*17/*17), this is a moderate recommendation.

Adjustments to citalopram or escitalopram therapy are not warranted based on CYP2C19 status for those who are CYP2C19 extensive metabolizers. Though CYP2C19 intermediate metabolizers may have elevated plasma concentrations, dose extrapolations suggest that minimal dose adjustments are warranted for intermediate metabolizers (1). Elevated concentrations of these drugs have been observed in poor metabolizers, which may increase the risk of adverse drug reactions (24-27). To potentially prevent an adverse effect, an alternative SSRI not extensively metabolized by CYP2C19 should be considered. If citalopram or escitalopram is warranted an initial dosage decrease of 50% should be considered (1). For citalopram, the FDA recommends a 50% dose reduction (or a maximum dose of 20 mg/day in adults) for CYP2C19 poor metabolizers due to risk of QT prolongation (the FDA recommendation does not apply to escitalopram) (6). Although limited data are available describing the relationship between SSRI concentrations and therapeutic effect and tolerability, this is a moderate recommendation due to apparent risk for arrhythmias combined with the FDA providing specific dose recommendations.

Pharmacokinetic data show reduced oral clearance of sertraline in CYP2C19 poor metabolizers (28, 29) but only slightly increased metabolism in ultrarapid metabolizers (28). Side effects in CYP2C19 poor metabolizers have also been reported to be more frequent than in normal metabolizers (30). Therefore, in CYP2C19 poor metabolizers a dose reduction of 50% is recommended or an alternative SSRI not extensively metabolized by CYP2C19 should be considered (Table 3). No dose adjustment is recommended for CYP2C19 ultrarapid metabolizers; however, if a patient is not responding to adequate maintenance doses of sertraline, consider an alternative SSRI not predominantly metabolized by CYP2C19. Due to the limited available evidence, this recommendation is optional.

Pediatrics

Data describing the relationship between CYP2D6 or CYP2C19 genotype and SSRI systemic exposure or steady state plasma concentrations in pediatric patients are scarce (Supplemental Data). Because CYP2D6 activity is fully mature by early childhood (31), it may be appropriate to extrapolate these recommendations to adolescents or possibly younger children with close monitoring. CYP2C19 activity may be increased in children relative to adults; therefore, these recommendations should be used with caution in children and accompanied by close monitoring. Ultimately, additional research and clinical trials in pediatric patients investigating the association between CYP2D6 or CYP2C19 and SSRI systemic exposure or treatment outcomes is needed.

Recommendations for Incidental Findings

Not applicable

Other considerations

Paroxetine and fluoxetine are strong inhibitors of CYP2D6, albeit involving different mechanisms (32). Several studies have suggested that CYP2D6 ultrarapid metabolizers may not undergo phenoconversion by paroxetine, though some of these studies were short in duration and may not be representative of steady-state conditions (15-18). CYP2D6 extensive and intermediate metabolizers may be more susceptible to paroxetine-induced phenoconversion (from extensive/intermediate to intermediate/poor metabolizers due to auto-inhibition). Evidence presented in Supplemental Table S8 demonstrates that paroxetine pharmacokinetic parameters are significantly different among CYP2D6 poor metabolizers when compared to extensive metabolizers. Some of these studies, though, are limited by relatively short study periods. (see Supplemental Material for more information).

Many of the SSRIs are substrates for other metabolic enzymes such as CYP1A2, CYP2C9 and CYP3A4. There is currently no strong evidence supporting gene-based dosing recommendations for other cytochrome P450 enzymes that metabolize SSRIs. There is increasing evidence that variations in the genes encoding the serotonin transporter (5-HTT, SLC6A4) and the serotonin 2A receptor (HTR2A) are associated with SSRI response and adverse effects (33). As additional studies are published, gene-based dosing recommendation for SLC6A4 and/or HTR2A may be warranted.

The guideline supplement contains examples of clinical decision support (CDS) tools that can be used within electronic health records (EHRs) to assist clinicians in applying genetic information to patient care for the purpose of drug therapy optimization (See Supplemental Material). Clinical implementation resources include cross-references for drug and gene names to widely-used terminologies and standardized nomenclature systems (Supplemental Tables S12 and S13), work flow diagrams (Supplemental Figures S2 and S3), tables that translate genotype test results into a predicted phenotype (Supplemental Tables S14 and S15), and example text for documentation in the EHR and point-of-care alerts (Supplemental Table S16).

Potential Benefits and Risks for the Patient

Existing CYP2D6 and/or CYP2C19 genotype results may provide the potential benefit of identifying patients who are at an increased risk of experiencing adverse drug reactions or therapeutic failure. A potential risk is the misinterpretation of genetic test results, as rare or novel variants are typically not interrogated. If an individual carries a rare variant, the actual phenotype may differ from the predicted phenotype. An individual's CYP2D6 and/or CYP2C19 metabolizer status may also depend on other factors including epigenetic phenomena, diet, co-morbidities, or comedications (34). Although CYP2D6 and/or CYP2C19 genotyping is usually reliable when performed in qualified laboratories, the possibility for error in genotyping, contamination, or mislabeling of the sample remains.

Caveats: Appropriate Use and/or Potential Misuse of Genetic Tests

Patients on a stable and effective dose of an SSRI most likely will not benefit from additional dose modifications based on CYP2D6 or CYP2C19 genotype results. Similar to all diagnostic tests, genetic tests are one of several pieces of clinical information that should be considered before initiating drug therapy.

Table 1. Assignment of Likely Phenotypes Based on Diplotypes.

a. Assignment of CYP2D6 predicted phenotypes
Likely phenotype	Activity Score	Genotypes	Examples of CYP2D6diplotypes
Ultrarapid metabolizer (∼1-2% of patients)a	> 2.0	An individual carrying duplications of functional alleles	*1/*1xN, *1/*2xN, *2/*2xNb
Extensive metabolizer (∼77-92% of patients)	2.0-1.0c	An individual carrying two normal function alleles or two decreased function alleles or one normal function and one no function allele or one normal function and one decreased function allele	*1/*1, *1/*2, *1/*4, *1/*5, *1/*9, *1/*41, *2/*2,*41/*41
Intermediate metabolizer (∼2-11% of patients)	0.5	An individual carrying one decreased function and one no function allele	*4/*10, *4/*41, *5/*9
Poor metabolizers (∼5-10% of patients)	0	An individual carrying only no functional alleles	*3/*4, *4/*4, *5/*5, *5/*6
b. Assignment of CYP2C19 predicted phenotypes
Likely phenotype		Genotypes	Examples of CYP2C19 diplotypes
Ultrarapid metabolizer (∼5-30% of patients)d		An individual carrying two increased function alleles or one normal function allele and one increased function allele	*17/*17, *1/*17
Extensive metabolizer (∼35-50% of patients)		An individual carrying two normal function alleles	*1/*1
Intermediate metabolizer (∼18-45% of patients)		An individual carrying one normal function allele or one increased function allele and one no function allele	*1/*2, *1/*3, *2/*17e
Poor metabolizer (∼2-15% of patients)		An individual carrying two no function alleles	*2/*2, *2/*3, *3/*3

^aCYP2D6 metabolizer status frequencies are based on data from Caucasians and may differ from other ethnicities. See Supplemental Tables S3 and S6 note for information on the chances of observing specific diplotypes in different major race/ethnic groups.

^bWhere 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.

^cPatients with an activity score of 1.0 may be classified as intermediate metabolizers by some reference laboratories.

^dCYP2C19 metabolizer status frequencies are based on average multi-ethnic frequency.

^eThe predicted metabolizer phenotype for the *2/*17 genotypes is a provisional classification. The currently available evidence indicates that the CYP2C19*17 increased function allele is unable to completely compensate for the no function CYP2C19*2 (35). See Supplemental Materials for a more comprehensive list of predicted metabolizer phenotypes.