Pharmacokinetics and pharmacodynamics of benidipine using a slow receptor-binding model

Summary Purpose: This study examined the relationship between the plasma concentration of benidipine, a long‐lasting antihypertensive agent with Ca2+‐channel‐blocking properties, and its cardiovascular effects (reduction in blood pressure and increase in heart rate) in order to assess the usefulness of pharmacokinetic–pharmacodynamic (PK‐PD) modelling in describing this relationship. Methods: Two groups of 24 healthy volunteers received either a 4‐ or 8‐mg benidipine hydrochloride tablet; 11 additional subjects received a placebo. Serial blood sampling and PD measurements were performed over 8 h thereafter. Plasma concentrations of benidipine were measured with a validated LC/MS/MS system, and the effects on blood pressure and heart rate were assessed during the same period. A two‐compartment open model with lag time was used to explain the PK properties, and the PD model was characterized by slow receptor binding, reflecting the binding of benidipine to the ion‐channel receptor. Results: Benidipine reached mean peak plasma concentrations of 1·04 and 3·85 ng/mL at 0·5 and 0·75 h after 4 and 8 mg doses, respectively. Peak cardiovascular effects were detected approximately 2 h after the administration of either dose. Maximal decreases in diastolic blood pressure with 4 and 8 mg of benidipine were 7·79 and 14·75 mmHg, respectively, and maximal increases in heart rate were 7·32 and 17·56 bpm, respectively. No significant changes in systolic blood pressure were observed. The cardiovascular effects were analysed according to a slow receptor‐binding model. Conclusions: The tested PK‐PD model successfully described the relationship between the plasma concentration of benidipine and its cardiovascular effects.