Search

The prodrug, clopidogrel, plays an important role in the prevention of thrombotic events in patients undergoing coronary stenting. However, a substantial number of atherothrombotic events still occur, which can partially be explained by heightened residual platelet reactivity. Several studies report that the genetic variation in CYP2C19 (*2) is associated with an impaired response to clopidogrel.To evaluate the effect of genetic variants affecting clopidogrel's absorption (ABCB1 C1236T, G2677T/A, C3435T), metabolism (CYP2C9*2, *3, CYP2C19*3, CYP3A4*1B, and CYP3A5*3), and pharmacodynamics (P2Y1 A1622G) on top of the influence of CYP2C19*2 on platelet reactivity in patients undergoing elective coronary stenting on dual antiplatelet therapy.Platelet function was assessed by light transmittance aggregometry and VerifyNow P2Y12 assay in 428 consecutive patients. Patients were either on chronic clopidogrel maintenance therapy (75 mg/day foror =5 days before the intervention) or received a 300 mg clopidogrel loading dose (1-5 days before the intervention, followed by 75 mg/day). Linear and logistic regressions were used to assess the associations between genetic variants and platelet reactivity and poor responder status.In both the treatment groups, CYP2C19*2-carriage was associated with higher platelet reactivity (P0.002) and poor responder status; 75 mg group: adjusted odds ratio (ORadj): 3.8, 95% confidence interval (CI): 2.0-7.2, 300 mg group: ORadj: 4.1, 95% CI: 1.6-10.4. In the 300 mg group, CYP2C9*3-carriage was associated with higher platelet reactivity (P0.05) and poor responder status (ORadj: 11.1, 95% CI: 1.6-78.8, P=0.016).Besides CYP2C19*2, the variant allele CYP2C9*3 plays an important role in the response to clopidogrel in patients on dual antiplatelet therapy undergoing coronary stenting.

Despite well-known differences in drug response between children and adults, dosing guidelines for children are usually developed by extrapolating the results from studies in adults. Instead of body weight, insight into the pharmacokinetics and pharmacodynamics of drugs should serve as the basis for dosing in children. In studies into drug dosing in children, the 'population approach' should be chosen to minimize the burden for the child. With a population approach, the covariates that affect the pharmacokinetics and pharmacodynamics of drugs can be identified in a covariate analysis; examples of covariates include body weight, age, degree of illness and genetic factors. Drugs that serve as a model for a specific elimination route provide the basis for individualized dosing guidelines for children.