C.M. Stein

Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy: 2013 Update

Cytochrome P450 (CYP)2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 loss‐of‐function alleles impair formation of active metabolites, resulting in reduced platelet inhibition. In addition, CYP2C19 loss‐of‐function alleles confer increased risks for serious adverse cardiovascular (CV) events among clopidogrel‐treated patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI). Guideline updates include emphasis on appropriate indication for CYP2C19 genotype–directed antiplatelet therapy, refined recommendations for specific CYP2C19 alleles, and additional evidence from an expanded literature review (updates at http://www.pharmgkb.org).

Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 Genotypes and Warfarin Dosing

Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the cytochrome P450–2C9 (CYP2C9) and vitamin K–epoxide reductase complex (VKORC1) enzymes, in addition to known nongenetic factors, account for ~50% of warfarin dose variability. The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 genotype data for estimating therapeutic warfarin dose to achieve an INR of 2–3, should genotype results be available to the clinician. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health Pharmacogenomics Research Network develops peer–reviewed gene–drug guidelines that are published and updated periodically on http://www.pharmgkb.org based on new developments in the field. 1

Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing.

Thiopurine methyltransferase (TPMT) activity exhibits monogenic co‐dominant inheritance, with ethnic differences in the frequency of occurrence of variant alleles. With conventional thiopurine doses, homozygous TPMT‐deficient patients (~1 in 178 to 1 in 3,736 individuals with two nonfunctional TPMT alleles) experience severe myelosuppression, 30–60% of individuals who are heterozygotes (~3–14% of the population) show moderate toxicity, and homozygous wild‐type individuals (~86–97% of the population) show lower active thioguanine nucleolides and less myelosuppression. We provide dosing recommendations (updates at http://www.pharmgkb.org) for azathioprine, mercaptopurine (MP), and thioguanine based on TPMT genotype.

Clinical Pharmacogenetics Implementation Consortium Guidelines for Cytochrome P450-2C19 (CYP2C19) Genotype and Clopidogrel Therapy

CYP2C19 is one of the principal enzymes involved in the bioactivation of the antiplatelet prodrug clopidogrel. A common loss‐of‐function allele, CYP2C19*2 (c.681G>A; rs4244285), is associated with increased risk for serious adverse cardiovascular events in both heterozygous and homozygous patients (~25–50% of the population) with acute coronary syndromes (ACSs) who are receiving clopidogrel, particularly among those undergoing percutaneous coronary intervention (PCI). We provide evidence from published literature and guidelines for CYPC19 genotype–directed antiplatelet therapy (periodically updated at http://www.pharmgkb.org).

Clinical Pharmacogenetics Implementation Consortium Guidelines for Thiopurine Methyltransferase Genotype and Thiopurine Dosing: 2013 Update

The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Methyltransferase Genotype and Thiopurine Dosing was originally published in March 2011. We reviewed recent literature and concluded that although relevant new evidence has been generated, none of the evidence would change the primary dosing recommendations in the original guideline; therefore, the original publication remains clinically current. Up‐to‐date information on thiopurine methyltransferase (TPMT) gene alleles and nomenclature can be found at PharmGKB (http://www.pharmgkb.org).

Integration of genetic, clinical, and INR data to refine warfarin dosing

Well‐characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one‐third of the variability in therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R2 of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R2 of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R2 was 26–43% with the clinical algorithm and 42–58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.

A common β1-adrenergic receptor polymorphism (Arg389Gly) affects blood pressure response to β-blockade

A common polymorphism of the β1‐adrenergic receptor Arg389Gly markedly affects function in vitro, but little is known about its in vivo significance.

Adipocytokines in Systemic Lupus Erythematosus: Relationship to Inflammation, Insulin Resistance and Coronary Atherosclerosis

We tested the hypothesis that concentrations of adipocytokines are altered in SLE and associated with coronary atherosclerosis, insulin resistance and inflammation. Concentrations of resistin, leptin, adiponectin and visfatin were measured in 109 patients with SLE and 78 control subjects. Coronary calcification was measured using electron beam-computed tomography, and insulin resistance was defined by the homeostasis model assessment index. Concentrations of adiponectin (28.7 ± 17.9 vs 22.0 ± 15.3 μg/mL, P = 0.003), leptin (41.1 ± 49.9 vs 19.8 ± 24.6 ng/mL, P < 0.001) and visfatin (7.5 ± 10.5 vs 4.5 ± 2.8 ng/mL, P < 0.001) were higher in patients with SLE than in controls. These differences remained significant after adjustment for age, race, sex and body mass index (BMI; all P values < 0.02). Concentrations of resistin (10.7 ± 7.6 vs 9.1 ± 5.1 ng/mL, P = 0.41) did not differ in patients and controls. In patients with SLE, leptin was positively associated with BMI (ρ = 0.80, P < 0.001), insulin resistance (ρ = 0.46, P < 0.001) and C-reactive protein (CRP) (ρ = 0.30, P = 0.002), whereas adiponectin was negatively associated with the same factors (ρ = –0.40, P < 0.001; ρ = −0.38, P < 0.001; ρ = –0.22, P = 0.02, respectively). None of the adipocytokines were associated with coronary atherosclerosis in SLE. In conclusion, patients with SLE have increased concentrations of adiponectin, leptin and visfatin. Lower concentrations of adiponectin and higher concentrations of leptin are associated with insulin resistance, BMI and CRP in patients with SLE.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing

Tacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose‐adjusted trough concentrations of tacrolimus as compared with those who are CYP3A5 nonexpressers (poor metabolizers), possibly delaying achievement of target blood concentrations. We summarize evidence from the published literature supporting this association and provide dosing recommendations for tacrolimus based on CYP3A5 genotype when known (updates at www.pharmgkb.org).

Assessment of Adherence to and Persistence on Disease-Modifying Antirheumatic Drugs (DMARDs) in Patients With Rheumatoid Arthritis

Objective:Biologic disease-modifying antirheumatic drugs (DMARDs) are efficacious for treating rheumatoid arthritis (RA). However, measurements of relative effectiveness, including treatment adherence and persistence, are lacking. We evaluated adherence and persistence during new episodes of use of traditional and biologic DMARDs. Methods:Using Tennessee Medicaid databases (1995–2004), we assembled a retrospective cohort of patients diagnosed with RA, and identified new episodes of use for 12 DMARD regimens. We evaluated persistence through survival analyses, and adherence within episodes through the medication possession ratio. A risk score was included in the analyses to account for measured confounders. Results:We identified 14,932 patients with RA; 6018 patients had 10,547 episodes of new use of DMARDs. Considering methotrexate as the reference and after adjustment for measured confounders, episodes of new use of sulfasalazine [adjusted hazard ratio (aHR) = 1.59; 95% confidence interval (CI) = 1.47–1.72] and infliximab alone (aHR = 1.37, 95% CI = 1.09–1.73) were more likely to be discontinued; and new episodes of etanercept (aHR = 0.82, 95% CI = 0.73–0.92) and methotrexate + adalimumab (aHR = 0.63, 95% CI = 0.48–0.84) were less likely to be discontinued. Compared with methotrexate, adherence was higher for leflunomide, infliximab, etanercept, and adalimumab and lower for sulfasalazine and all combined therapies. Conclusions:We developed an approach to assess persistence on and adherence to the most common DMARD therapies. In this large cohort, persistence and adherence to leflunomide and most biologic DMARD therapies were at least comparable to methotrexate. Adherence was lower for sulfasalazine and all combined therapies.