Children's Mercy Kansas City Children's Mercy Kansas City
SHARE @ Children's Mercy SHARE @ Children's Mercy
Manuscripts, Articles, Book Chapters and Other Papers
7-1-2017
Clinical pharmacogenetics implementation consortium guideline Clinical pharmacogenetics implementation consortium guideline
(CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of
tricyclic antidepressants: 2016 update. tricyclic antidepressants: 2016 update.
J K. Hicks
K Sangkuhl
J J. Swen
V L. Ellingrod
D J. Müller
See next page for additional authors
Follow this and additional works at: https://scholarlyexchange.childrensmercy.org/papers
Part of the Medical Genetics Commons, Medical Pharmacology Commons, and the Pharmaceutical
Preparations Commons
Recommended Citation Recommended Citation
Hicks JK, Sangkuhl K, Swen JJ, et al. Clinical pharmacogenetics implementation consortium guideline
(CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin
Pharmacol Ther. 2017;102(1):37-44. doi:10.1002/cpt.597
This Article is brought to you for free and open access by SHARE @ Children's Mercy. It has been accepted for
inclusion in Manuscripts, Articles, Book Chapters and Other Papers by an authorized administrator of SHARE @
Children's Mercy. For more information, please contact hlsteel@cmh.edu.
Creator(s) Creator(s)
J K. Hicks, K Sangkuhl, J J. Swen, V L. Ellingrod, D J. Müller, K Shimoda, J R. Bishop, E D. Kharasch, T C.
Skaar, Andrea Gaedigk, H M. Dunnenberger, T E. Klein, K E. Caudle, and J C. Stingl
This article is available at SHARE @ Children's Mercy: https://scholarlyexchange.childrensmercy.org/papers/514
Clinical Pharmacogenetics Implementation Consortium
Guideline (CPIC®) for CYP2D6 and CYP2C19 Genotypes and
Dosing of Tricyclic Antidepressants: 2016 Update
J. Kevin Hicks
1
, Katrin Sangkuhl
2
, Jesse J. Swen
3
, Vicki L. Ellingrod
4
, Daniel J. Müller
5
,
Kazutaka Shimoda
6
, Jeffrey R. Bishop
7
, Evan D. Kharasch
8
, Todd C. Skaar
9
, Andrea
Gaedigk
10
, Henry M. Dunnenberger
11
, Teri E. Klein
2
, Kelly E. Caudle
12
, and Julia C. Stingl
13
1
DeBartolo Family Personalized Medicine Institute, Division of Population Science, H. Lee Moffitt
Cancer Center and Research Institute, Tampa, Florida, USA
2
Department of Genetics, Stanford
University, Stanford, California, USA
3
Department of Clinical Pharmacy and Toxicology, Leiden
University Medical Center, Leiden, The Netherlands
4
Department of Clinical, Social and
Administrative Sciences, College of Pharmacy, and Department of Psychiatry, School of
Medicine, University of Michigan, Ann Arbor, Michigan, USA
5
Campbell Family Mental Health
Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of
Psychiatry, University of Toronto, Toronto, ON, Canada
6
Department of Psychiatry, Dokkyo
Medical University, Japan
7
Department of Experimental and Clinical Pharmacology, College of
Pharmacy, and Department of Psychiatry, College of Medicine, University of Minnesota,
Minneapolis, MN, USA
8
Division of Clinical and Translational Research, Department of
Anesthesiology, Washington University in St. Louis, St. Louis, Missouri, USA
9
Division of Clinical
Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN,
USA
10
Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children’s Mercy-,
Kansas City, Missouri and Department of Pediatrics, University of Missouri-Kansas City, Kansas
City, Missouri, USA
11
Center for Molecular Medicine, NorthShore University HealthSystem,
Corresponding Author: Julia C. Stingl, MD, Division of Research, Federal Institute of Drugs and Medical Devices And University of
Bonn Medical School, Kurt-Georg-Kiesinger-Allee 3, D-53175 Bonn, Germany, Phone: +49 (0)228-99-307-3570,
Julia.Stingl@bfarm.de.
DISCLAIMER
CPIC guidelines reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written
and are intended only to assist clinicians in decision making and to identify questions for further research. New evidence may have
emerged since the time a guideline was submitted for publication. Guidelines are limited in scope and are not applicable to
interventions or diseases not specifically identified. Guidelines do not account for all individual variations among patients and cannot
be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care
provider to determine the best course of treatment for a patient. Adherence to any guidelines is voluntary, with the ultimate
determination regarding its application to be made solely by the clinician and the patient. CPIC assumes no responsibility for any
injury to persons or damage to persons or property arising out of or related to any use of CPIC’s guidelines, or for any errors or
omissions.
CPIC is a registered service mark of the U.S. Department of Health & Human Services (HHS).
CONFLICT OF INTEREST
A.G. is a paid consultant of Millennium Laboratories. T.E.K is a paid scientific advisor to the Rxight
™
Pharmacogenetic Program.
K.S. has received research support from Shionogi & Co., Ltd., Eli Lilly Japan, K.K., Yoshitomi Pharmaceutical Industries, Ltd., Meiji
Seika Pharma Co., Ltd., Eisai Co., Ltd., Pfizer Inc., GlaxoSmithKlein K.K., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., and
Takeda Pharmaceutical Co., Ltd. and honoraria from Kowa Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Meiji
Seika Pharma Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Ono Pharmaceutical Co., Ltd., GlaxoSmithKlein K.K., and Eisai Co.,
Ltd
All other authors declare no conflict of interest.
HHS Public Access
Author manuscript
Clin Pharmacol Ther
. Author manuscript; available in PMC 2018 June 20.
Published in final edited form as:
Clin Pharmacol Ther
. 2017 July ; 102(1): 37–44. doi:10.1002/cpt.597.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
Evanston, IL, USA
12
Department of Pharmaceutical Sciences, St. Jude Children’s Research
Hospital, Memphis, Tennessee, USA
13
Division of Research, Federal Institute of Drugs and
Medical Devices, Bonn, Germany
Abstract
CYP2D6
and
CYP2C19
polymorphisms affect the exposure, efficacy and safety of tricyclic
antidepressants (TCAs), with some drugs being affected by CYP2D6 only (e.g., nortriptyline and
desipramine) and others by both polymorphic enzymes (e.g., amitriptyline, clomipramine,
doxepin, imipramine, and trimipramine). Evidence is presented for
CYP2D6
and
CYP2C19
genotype-directed dosing of TCAs. This document is an update to the 2012 Clinical
Pharmacogenetics Implementation Consortium (CPIC) guideline for
CYP2D6
and
CYP2C19
Genotypes and Dosing of Tricyclic Antidepressants.
Keywords
CYP2D6; CYP2C19; pharmacogenetics; tricyclic antidepressants; amitriptyline; clomipramine;
desipramine; doxepin; imipramine; nortriptyline; and trimipramine
INTRODUCTION
Observed inter-individual differences in tricyclic antidepressant (TCA) pharmacokinetic
parameters and treatment outcomes are associated with
CYP2D6
and/or
CYP2C19
genetic
variation. The purpose of this guideline is to provide information to allow the interpretation
of existing
CYP2D6
and/or
CYP2C19
genotyping results to guide TCA dosing and
selection. Other clinical variables that may influence TCA therapy as well as genotyping
cost-effectiveness are beyond the scope of this document. CPIC guidelines are periodically
updated at https://cpicpgx.org/guidelines/ and http://www.pharmgkb.org.
FOCUSED LITERATURE REVIEW
A systematic literature review focused on
CYP2D6
and
CYP2C19
genetic variations and
their relevance to gene-based dosing of TCAs was conducted (see Supplementary Data
online). This guideline was developed based on interpretation of the literature by the authors
and by experts in the field.
GENES: CYP2D6 AND CYP2C19
CYP2D6 background
The
CYP2D6
gene is highly polymorphic. Over 100 known allelic variants and subvariants
have been identified, and there are substantial ethnic differences in observed allele
frequencies (
CYP2D6
Allele Definition Table and CYP2D6 Frequency Table (1)). 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 or
Hicks et al.
Page 2
Clin Pharmacol Ther
. Author manuscript; available in PMC 2018 June 20.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
duplications, many clinical laboratories also report copy number. Deletions are indicated by
the
CYP2D6*5
allele, and gene duplications are denoted by an “
xN
” following the allele
(e.g.,
CYP2D6*1xN
, where
xN
represents the number of
CYP2D6
gene copies).
CYP2C19 background
Similar to
CYP2D6
, the
CYP2C19
gene is highly polymorphic; over 35 known allelic
variants and subvariants have been identified (3) (
CYP2C19
Allele Definition Table (4)).
Although there are ethnic differences in allele frequencies (
CYP2C19
Frequency Table (4)),
the majority of patients will carry a
CYP2C19*1
,
*2,*3
or
*17
allele (5).
CYP2C19*1
is the
wild-type allele encoding a fully functional enzyme.
CYP2C19*2
-
*8
are no function alleles
of which
CYP2C19*2
is the most frequently observed, though
CYP2C19*3
is more
common among individuals of Asian ancestry (3, 5). The
CYP2C19*17
allele, defined by a
variant in the gene promoter region, causes enhanced gene transcription resulting in greater
metabolic capacity (6) and is therefore classified as an increased function allele.
Genetic test interpretation
Clinical laboratories usually interrogate 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 gene locus of either
CYP2D6
or
CYP2C19
(5). 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
).
The more frequently observed alleles and their functional status can be found in the
CYP2D6
(1) and
CYP2C19
Allele Definition Tables (4).
Scoring systems have been developed in an attempt to provide a uniform approach to
quantitate the predicted functional status of
CYP2D6
alleles as follows: 1 for normal
function, 0.5 for decreased function, and 0 for no function alleles (see Supplemental
Material;
CYP2D6
Allele Definition Table (1)) (2, 7). The activity value for each allele of
the diplotype is totaled to provide a
CYP2D6
activity score. If
CYP2D6
gene duplications
are detected, the activity value of the duplicated allele is multiplied by the number of
duplications present before calculating the activity score (Table 1, Supplemental Tables S1
and S2). See the Supplement for further explanation.
Patients with two normal function
CYP2C19
alleles are categorized as normal metabolizers
and individuals carrying one or two no function alleles are considered intermediate and poor
metabolizers, respectively (Table 1). Limited data suggest that
CYP2C19*17
may not
compensate for no function alleles such as the
CYP2C19*2
allele (8). Therefore, patients
carrying the
CYP2C19*17
increased function allele in combination with a no function allele
are considered intermediate metabolizers. These phenotype assignments are analogous to the
CPIC guideline for selective serotonin reuptake inhibitors (3). See Supplement for
discussion regarding CYP2C19 rapid metabolizer phenotype.
Reference laboratories use varying methods to assign phenotypes. Before pharmacotherapy
modifications are made based upon this guideline, it is advisable to determine a patient’s
phenotype as described above.
Hicks et al.
Page 3
Clin Pharmacol Ther
. Author manuscript; available in PMC 2018 June 20.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript