Gene:

CYP2C19

cytochrome P450, family 2, subfamily C, polypeptide 19

Guidelines regarding the use of pharmacogenomic tests in dosing for clopidogrel have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).

Download: article and supplement

Excerpt from the clopidogrel dosing guidelines:

The table below summaries the therapeutic CPIC guidelines for clopidogrel based on CYP2C19 phenotype for patients with acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI) initiating antiplatelet therapy. These guidelines have been limited to the CYP2C19*2 allele (rs4244285). At the time of writing these guidelines, only the CYP2C19*2 allele has been adequately studied with respect to clinical outcomes on clopidogrel; other variants are too rare, have not been studied, or have resulted in inconclusive findings. In addition to the CYP2C19*2 allele, many clinical genotyping platforms include other variant alleles (*3-*8, *17) that may alter the interpretation of a patient's predicted metabolizer phenotype. For some rare genotype combinations (e.g.*2/*17) metabolic phenotypes are difficult to predict.

Clopidogrel therapy based on CYP2C19 phenotype for ACS/PCI patients initiating antiplatelet therapy:

¹ The CYP2C19*17 allele (rs12248560) may be associated with increased risk of bleeding (see article for reference).

An important caveat for all genotyping tests is that the "wild-type" (*1) status is reported if all other alleles that are measured are absent. Some genotype tests do not interrogate the rare loss of function alleles and therefore, if present, they may be erroneously reported as "wild type". Furthermore, in human DNA, it is always possible that a new, previously undiscovered (and therefore un-interrogated) site of variation may confer altered enzyme function in an individual, and thus lead to the rare possibility of a loss-of-function allele being erroneously called as "wild-type" (*1). The guidelines do not focus on demographic and other clinical variables, such as adherence to therapy, age, diabetes mellitus, obesity, smoking, and concomitant use of other drugs that may influence clopidogrel efficacy and clinical decision making; see article.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for citalopram based on CYP2C19 genotype. They conclude to monitor plasma concentration and titrate dose to a maximum of 150% in response to efficacy and adverse drug event or select alternative drug (e.g. fluoxetine, paroxetine) for the CYP2C19 UM phenotype.

• *See Methods or PMID: 18253145 for definition of "good quality."
• Please see attached PDF for detailed information about the evaluated studies: Citalopram CYP2C19

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for clopidogrel based on the CYP2C19 genotype. For the CYP2C19 PM and IM phenotype they conclude an increased risk for reduced response to clopidogrel and recommend to consider an alternative drug. Prasugrel is not or to a much smaller extent metabolized by CYP2C19 but is associated with an increased bleeding risk compared to clopidogrel.

• *See Methods or PMID: 18253145 for definition of "good quality."
• #wherever one or more of the "good quality" criteria was missing, the quality of the study was considered to be "moderate"

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for escitalopram based on the CYP2C19 genotype. They conclude to monitor plasma concentration and titrate dose to a maximum of 150% in response to efficacy and adverse drug event or select alternative drug (e.g. fluoxetine, paroxetine) for the CYP2C19 UM phenotype.

• *See Methods or PMID: 18253145 for definition of "good quality."
• Please see attached PDF for detailed information about the evaluated studies: Escitalopram CYP2C19

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for esomeprazole based on CYP2C19 genotype. For the CYP2C19 UM phenotype, they conclude to be extra alert to insufficient response and recommend to consider dose increase by 50-100%.

• *See Methods or PMID: 18253145 for definition of "good quality."

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for imipramine based on CYP2C19 genotype.

• #See Methods or PMID: 18253145 for definition of "moderate" quality.
• Please see attached PDF for detailed information about the evaluated studies: Imipramine CYP2C19

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for lansoprazole based on CYP2C19 genotype. For the CYP2C19 UM phenotype, they conclude to be extra alert to insufficient response and recommend to consider dose increase by 200%.

• *See Methods or PMID: 18253145 for definition of "good quality."

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for moclobemide based on CYP2C19 genotype. They conclude that there are no recommendations at this time.

• #See Methods or PMID: 18253145 for definition of "moderate" quality.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for omeprazole based on CYP2C19 genotype. For the CYP2C19 UM phenotype, they conclude to be extra alert to insufficient response and recommend to consider dose increase by 100-200%.

• * and # See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
• Please see attached PDF for detailed information about the evaluated studies: Omeprazole CYP2C19

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for pantoprazole based on CYP2C19 genotype. For the CYP2C19 UM phenotype, they conclude to be extra alert to insufficient response and recommend to consider dose increase by 400%.

• #See Methods or PMID: 18253145 for definition of "moderate" quality.

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for rabeprazole based on CYP2C19 genotype. They conclude that there are no recommendations at this time.

• *See Methods or PMID: 18253145 for definition of "good quality."

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for sertraline based on CYP2C19 genotype.

• *See Methods or PMID: 18253145 for definition of "moderate" quality.
• Please see attached PDF for detailed information about the evaluated studies: Sertraline CYP2C19

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for voriconazole based on CYP2C19 genotype. They conclude to monitor serum concentration for patients carrying the CYP2C19 PM or IM phenotype.

• *See Methods or PMID: 18253145 for definition of "moderate" quality.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Carisoprodol.

Excerpt from the Carisoprodol drug label:
"Patients with Reduced CYP2C19 Activity: Carisoprodol should be used with caution in patients with reduced CYP2C19 activity. Published studies indicate that patients who are poor CYP2C19 metabolizers have a 4-fold increase in exposure to carisoprodol, and concomitant 50% reduced exposure to meprobamate compared to normal CYP2C19 metabolizers. The prevalence of poor metabolizers in Caucasians and African Americans is approximately 3-5% and in Asians is approximately 15-20%."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Carisoprodol drug label PDF.

The clopidogrel label highlights the pharmacogenetics of this drug.

Excerpt from the clopidogrel drug label:

The effectiveness of Plavix is dependent on its activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19 [see Warnings and Precautions (5.1)]. Plavix at recommended doses forms less of that metabolite and has a smaller effect on platelet function in patients who are CYP2C19 poor metabolizers. Poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with Plavix at recommended doses exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function. Tests are available to identify a patient's CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy [see Clinical Pharmacology (12.5)]. Consider alternate treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers [see Dosage and Administration (2.3)].

Twenty-one studies involving 4,520 subjects have shown that CYP2C19*2, CYP2C19*3, and other CYP2C19 loss-of-function alleles are associated with diminished antiplatelet responses to treatment with clopidogrel. CYP2C19 participates in the formation of both the active metabolite of clopidogrel and the 2-oxo-clopidogrel intermediate metabolite. Individuals with CYP2C19 loss-of-function alleles have reduced exposure to the active metabolite of clopidogrel, leading to less platelet inhibition or higher residual platelet reactivity. Key publications on pharmacogenetic studies of response to clopidogrel include: [Article:19106083, 19106084, 19108880, 19193675@PubMed].

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the clopidogrel drug label, updated 3/2010.

Diazepam is used mainly for treatment of anxiety and anxiety disorders and also for treatment of other issues including seizures, muscle spasms and irritable bowel syndrome. CYP2C19 is involved in its metabolism.

Excerpts from the Diazepam drug label:

"Diazepam is N-demethylated by CYP3A4 and 2C19 to the active metabolite N-desmethyldiazepam, and is hydroxylated by CYP3A4 to the active metabolite temazepam."

"There is a potentially relevant interaction between diazepam and compounds which inhibit certain hepatic enzymes (particularly
cytochrome P450 3A and 2C19."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Diazepam drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Esomeprazole is a proton pump inhibitor and entantiomer of omeprazole. It is metabolized in the liver by CYP2C19 and CYP3A4 (see Proton Pump Inhibitor Pathway).

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with esomeprazole.

Excerpt from the esomeprazole (Nexium) drug label:
"Esomeprazole may potentially interfere with CYP 2C19, the major esomeprazole metabolizing enzyme. Coadministration of esomeprazole 30 mg and diazepam, a CYP 2C19 substrate, resulted in a 45% decrease in clearance of diazepam. Concomitant administration of esomeprazole and a combined inhibitor of CYP 2C19 and CYP 3A4, such as voriconazole, may result in more than doubling of the esomeprazole exposure. Dose adjustment of esomeprazole is not normally required."

"CYP 2C19 isoenzyme exhibits polymorphism in the metabolism of esomeprazole, since some 3% of Caucasians and 15 to 20% of Asians lack CYP 2C19 and are termed Poor Metabolizers. At steady state, the ratio of AUC in Poor Metabolizers to AUC in the rest of the population (Extensive Metabolizers) is approximately 2."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the esomeprazole (Nexium) drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Rabeprazole is a proton-pump inhibitor used for treatment of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD). CYP2C19 poor metabolizer genotypes may have lower suppression of gastric acid as compared to more extensive metabolizers.

Excerpts from the rabeprazole drug label:

"In a clinical study in Japan evaluating rabeprazole in patients categorized by CYP2C19 genotype (n=6 per genotype category), gastric acid suppression was higher in poor metabolizers as compared to extensive metabolizers. This could be due to higher rabeprazole plasma levels in poor metabolizers."

"CYP2C19 exhibits a known genetic polymorphism due to its deficiency in some sub-populations (e.g. 3 to 5% of Caucasians and 17 to 20% of Asians). Rabeprazole metabolism is slow in these sub-populations, therefore, they are referred to as poor metabolizers of the drug."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Rabeprazole drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Voriconazole is an antifungal used to treat serious infections of Aspergillus fumigatu, Candida, Scedosporium, Fusarium and other species. Voriconazole is metabolized in the liver by CYP2C19, CYP2C9 and CYP3A4. It also influences expression of metabolizing enzymes and interacts with several other drugs.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with Voriconazole.

Excerpt from the Voriconazole (VFEND) drug label:
"Inhibitors and inducers of CYP3A4, CYP2C9, and CYP2C19 may alter VFEND concentrations. Adjust the VFEND dose and monitor for adverse events or lack of efficacy."

"VFEND may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce doses of and monitor for lack of efficacy or adverse events associated with drugs that are substrates of these enzymes."

"In vivo studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism. For example, 1520% of Asian populations may be expected to be poor metabolizers. For Caucasians and Blacks, the prevalence of poor metabolizers is 35%. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolizers have, on average, 4-fold higher voriconazole exposure (AUCt) than their homozygous extensive metabolizer counterparts. Subjects who are heterozygous extensive metabolizers have, on average, 2-fold higher voriconazole exposure than their homozygous extensive metabolizer counterparts."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Voriconazole drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Drospirenone and ethinyl estradiol (Yasmin) is a combined oral contraceptive drug.

The FDA recommends, but does not require, genetic testing prior to initiating or reinitiating treatment with drospirenone and ethinyl estradiol.

Excerpt from the drospirenone and ethinyl estradiol (Yasmin) drug label:
"In in vitro studies DRSP did not affect turnover of model substrates of CYP1A2 and CYP2D6, but had an inhibitory influence on the turnover of model substrates of CYP1A1, CYP2C9, CYP2C19 and CYP3A4 with CYP2C19 being the most sensitive enzyme."

"The potential effect of DRSP on CYP2C19 activity was investigated in a clinical pharmacokinetic study using omeprazole as a marker substrate. In the study with 24 postmenopausal women including 12 women with homozygous (wild type) CYP2C19 genotype and 12 women with heterozygous CYP2C19 genotype the daily oral administration of 3 mg DRSP for 14 days did not affect the oral clearance of omeprazole (40 mg, single oral dose). Based on the available results of in vivo and in vitro studies it can be concluded that, at clinical dose level, DRSP shows little propensity to interact to a significant extent with cytochrome P450 enzymes."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Drospirenone and ethinyl estradiol (Yasmin) drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Nelfinavir is a protease inhibitor which is used in combination with other medications to treat human immunodeficiency virus (HIV) infection by slowing the spread of the infection within the body. It is metabolized by cytochrome P-450 enzymes, mainly CYP3A and CYP2C19.

Excerpts from the Nelfinavir drug label:

"Nelfinavir is an inhibitor of the CYP3A enzyme. Coadministration of VIRACEPT and drugs primarily metabolized by CYP3A may result in increased plasma concentrations of the other drug that could prolong its therapeutic and adverse effects."

"Nelfinavir is metabolized by CYP3A and CYP2C19. Coadministration of VIRACEPT and drugs that induce CYP3A or CYP2C19 may decrease nelfinavir plasma concentrations and reduce its therapeutic effect. Coadministration of VIRACEPT and drugs that inhibit CYP3A or CYP2C19 may increase nelfinavir plasma concentrations."

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Nelfinavir drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.