Our results demonstrate that PON1 does not mediate clopidogrel active metabolite formation or antiplatelet action, while CYP2C19 activity and genotype remains a predictor of clopidogrel pharmacokinetics and antiplatelet response.

Single-nucleotide polymorphisms in genes that affect warfarin metabolism (cytochrome P450 2C9 gene, CYP2C9) and response (vitamin K epoxide reductase complex 1 gene, VKORC1) have an important influence on warfarin therapy, particularly during initiation; however, there is a lack of consensus regarding the optimal pharmacogenetics-based initiation strategy. We conducted a prospective cohort study in which patients requiring warfarin therapy for atrial fibrillation or venous thromboembolism were initiated with a novel pharmacogenetics-initiation protocol (WRAPID, Warfarin Regimen using A Pharmacogenetics-guided Initiation Dosing) that incorporated loading and maintenance doses based on genetics, clinical variables, and response (n ‫؍‬ 167, followed up for 90 days), to assess the influence of genetic variations on anticoagulation responses. Application of the WRAPID algorithm resulted in a negligible influence of genetic variation in VKORC1 or CYP2C9 on time to achievement of first therapeutic response (P ‫؍‬ .52, P ‫؍‬ .28) and risk of overanticoagulation (P ‫؍‬ .64, P ‫؍‬ .96). After adjustment for covariates, time to stable anticoagulation was not influenced by VKORC1 or CYP2C9 genotype. Importantly, time spent within or above the therapeutic range did not differ among VKORC1 and CYP2C9 genotype groups. Moreover, the overall time course of the anticoagulation response among the genotype groups was similar and predictable. We demonstrate the clinical utility of geneticsguided warfarin initiation with the WRAPID protocol to provide safe and optimal anticoagulation therapy for patients with atrial fibrillation or venous thromboembolism. (Blood. 2011;118(11):3163-3171)

Variable warfarin response during treatment initiation poses a significant challenge to providing optimal anticoagulation therapy. We investigated the determinants of initial warfarin response in a cohort of 167 patients. During the first nine days of treatment with pharmacogenetics-guided dosing, S-warfarin plasma levels and international normalized ratio were obtained to serve as inputs to a pharmacokinetic-pharmacodynamic (PK-PD) model. Individual PK (S-warfarin clearance) and PD (Imax) parameter values were estimated. Regression analysis demonstrated that CYP2C9 genotype, kidney function, and gender were independent determinants of S-warfarin clearance. The values for Imax were dependent on VKORC1 and CYP4F2 genotypes, vitamin K status (as measured by plasma concentrations of proteins induced by vitamin K absence, PIVKA-II) and weight. Importantly, indication for warfarin was a major independent determinant of Imax during initiation, where PD sensitivity was greater in atrial fibrillation than venous thromboembolism. To demonstrate the utility of the global PK-PD model, we compared the predicted initial anticoagulation responses with previously established warfarin dosing algorithms. These insights and modeling approaches have application to personalized warfarin therapy.

A continuing professional development (CPD) program for pharmacists practicing in community and team-based primary care settings was developed and evaluated using Moore’s framework for the assessment of continuing medical education. The program had three components: online lectures, a two-day training workshop, and patient case studies. Knowledge (pre-post multiple choice test); attitudes, readiness, and comfort with applying pharmacogenomics in their practices (pre-post surveys); and experiences of implementing pharmacogenomics in practice (semi-structured interviews) were assessed. Twenty-one of 26 enrolled pharmacists successfully completed the program, and were satisfied with their experience. Almost all achieved a score of 80% or higher on the post-training multiple choice test, with significantly improved scores compared to the pre-training test. Pre- and post-training surveys demonstrated that participants felt that their knowledge and competence increased upon completion of the training. In the follow-up, 15 pharmacists incorporated pharmacogenomics testing into care for 117 patients. Ten pharmacists participated in semi-structured interviews, reporting strong performance in the program, but some difficulty implementing new knowledge in their practices. This multi-component CPD program successfully increased pharmacists’ knowledge, readiness, and comfort in applying pharmacogenomics to patient care in the short-term, yet some pharmacists struggled to integrate this new service into their practices.