CONCENTRATION-EFFECT ANALYSIS OF VERAPAMIL - EVALUATION OF DIFFERENT APPROACHES

Plasma concentration and PR-interval prolongation were correlated afte r a single dose of 80 mg verapamil (trial A) and at steady-state durin g one dose interval (80 mg verapamil t.i.d.) on day 7 (trial B) and da y 14 (trial C) and the subsequent dose interval at the afternoon on da y 14 (trial D). The pharmacokinetic parameters of verapamil indicated a two-fold increase in AUC and C(max) at trial B and C when compared w ith the single dose application, but AUC and C(max) were considerably lesser during the afternoon dosing interval (trial D). For each subjec t, concentration/effect analysis was established: according to a linea r and a sigmoidal model, and using a plasma concentration vs effect ap proach (1) and a semiparametric effect-site concentration vs effect ap proach (2). The comparison of the two different approaches and models showed that in general, the concentration/effect analysis based on the linear model and with approach 2 gave the best description of the dro motropic response to verapamil for the majority of the individuals. Ho wever, approach 1 accounts for 30 to 50% of the concentration/effect c urve established in the data subsets of trial A to D, and about 40% of all curves in trial A, B and C can be more precisely described with t he E(max)-model, whereas almost all curves obtained in trial D were be st described by a linear model. A decrease in the responsiveness to ve rapamil at steady-state was indicated by both models, but more precise ly described by the parameters of the E(max)-model.