Concentration/effect analysis of verapamil: evaluation of different approaches

Plasma concentration and PR-interval prolongation were correlated after a single dose of 80 mg verapamil (trial A) and at steady-state during one dose interval (80 mg verapamil t.i.d.) on day 7 (trial B) and day 14 (trial C) and the subsequent dose interval at the afternoon on day 14 (trial D). The pharmacokinetic parameters of verapamil indicated a two-fold increase in AUC and Cmax at trial B and C when compared with the single dose application, but AUC and Cmax were considerably lesser during the afternoon dosing interval (trial D). For each subject, concentration/effect analysis was established: according to a linear and a sigmoidal model, and using a plasma concentration vs effect approach (1) and a semiparametric effect-site concentration vs effect approach (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 dromotropic response to verapamil for the majority of the individuals. However, approach 1 accounts for 30 to 50% of the concentration/effect curve 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 the Emax-model, whereas almost all curves obtained in trial D were best described by a linear model. A decrease in the responsiveness to verapamil at steady-state was indicated by both models, but more precisely described by the parameters of the Emax-model.