Pharmacokinetic‐pharmacodynamic modeling between pinacidil or pinacidil‐N‐oxide plasma levels and systemic and regional hemodynamic effects in healthy volunteers

Summary— Pinacidil (P) lowers blood pressure through peripheral vasodilation, but also induces dose‐dependent side‐effects. In a previous placebo‐controlled, randomized, double‐blind and crossover study, performed in six healthy male volunteers, we investigated the systemic and regional hemodynamic effects of a single oral administration of 25 mg of P (sustained‐release form) and measured the plasma concentrations of P and of its active metabolite, pinacidil‐N‐oxide (PO). In the present study, our goal has been to investigate the relationships between P and/or PO plasma concentrations and P administration effects on systolic, diastolic and mean arterial pressures (SAP, DAP, MAP), heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), brachial and carotid arteries' diameters (BAD, CAD), flows (BAF, CAF) and vascular resistances (BVR, CVR) which were assessed before and at different time intervals after drug intake. Concentration‐effect relationships were investigated using both linear and log‐linear multiple regression models with P, PO or both P and PO as independent variables (six models). Significant linear relationships were observed between P and/or PO and SAP, DAP, MAP, TPR, BAD, BAF, BVR, CAD and CVR. For example, TPR (dynes.s/cm 5 ) = 1308 – 3.031 × P (ng/ml), R = 0.57, P = 0.0037; BVR (mmHg.s/ml) = 58 – 0.261 × P (ng/ml), R = 0.56, P = 0.0042. Almost similar R values were obtained using P, PO, or both P and PO. The use of log‐linear models did not improve the fittings. We conclude that there are significant linear relationships between P plasma concentrations and most of P systemic and regional hemodynamic effects; this finding allows the determination of the best individual P dosage for inducing a given hemodynamic effect, and, using PO instead of P plasma concentrations does not improve the models and is thus useless.