Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants

Abstract

nature publishing groupPolymorphisms in CYP2D6 and CYP2C19 affect the efficacy and safety of tricyclics, with some drugs being affected by CYP2D6 only, and others by both polymorphic enzymes. Amitriptyline, clomipramine, doxepin, imipramine, and trimipramine are demethylated by CYP2C19 to pharmacologically active metabolites. These drugs and their metabolites, along with desipramine and nortriptyline, undergo hydroxylation by CYP2D6 to less active metabolites. Evidence from published literature is presented for CYP2D6 and CYP2C19 genotype-directed dosing of tricyclic antidepressants.The use of tricyclics to treat psychological disorders has declined in part because of the occurrence of undesirable side effects. Although tricyclics are still used to treat depression, 1 their main therapeutic use is often for pain management. 2,3 Interindividual differences in side effects and treatment response have been associated with variability of tricyclic plasma concentrations. 4,5 Because both enzymes influence plasma concentrations, the effectiveness and tolerability of tricyclics are affected by CYP2D6 metabolism and partially by CYP2C19 metabolism. 4 The purpose of this guideline is to provide information regarding how to use existing CYP2D6 and/or CYP2C19 genotyping test results to guide dosing of tricyclics for psychological disorders and pain management, focusing particularly on amitriptyline and nortriptyline.Optimal therapeutic plasma concentrations for the tricyclics have been defined. 6 Poor or ultrarapid metabolizers of CYP2D6 and CYP2C19 may have tricyclic plasma concentrations outside the recommended therapeutic range, thereby increasing the risk of treatment failure or side effects. 7-10 Therefore, this guideline takes into consideration both clinical outcomes and observed tricyclic plasma concentrations based on genotype/phenotype characteristics. Detailed guidelines for use of other laboratory tests including therapeutic drug monitoring of tricyclics are beyond the scope of this article. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health's Pharmacogenomics Research Network develops peer-reviewed gene-drug guidelines that are published and updated periodically at http://www.pharmgkb.org based on new developments in the field. FOCUSED LITERATURE REVIEWA systematic literature review focused on CYP2D6 and CYP2C19 genotyping and its relevance to gene-based dosing of tricyclics was conducted (see Supplementary Data online). This guideline was developed based on interpretation of the literature by the authors and experts in the field. GENES: CYP2D6 AND CYP2C19 CYP2D6 backgroundThe CYP2D6 gene is highly polymorphic. 11 More than 100 known allelic variants and subvariants have been identified, and there are substantial ethnic differences in observed allele frequencies (Supplementary Data online). The most commonly reported CYP2C19 backgroundSimilar to CYP2D6, the CYP2C19 gene is highly polymorphic; more than 30 known allelic variants and subvariants have been identif...

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