Importance of Oral Dosing Rate on the Hemodynamic and Pharmacokinetic Profile on Nilvadipine

Nilvadipine was administered as an oral solution formulation to 12 normotensive subjects in a three‐way randomized crossover study at at dose of 16 mg as three different dosing regimens: 1) as a single 16 mg dose, 2) as a 1.6 mg dose given hourly for 10 doses, and 3) as an initial dose of 4.8 mg, followed by 1.6 mg doses given every hour for seven additional doses. After each dose, clinical effects, hemodynamic changes and the pharmacokinetic profile of the drug were determined. The mean maximum changes in diastolic (DBP) and systolic (SBP) blood pressure and heart rate (HR) after dosing regimens 1, 2, and 3 were: −33, −13 and +46%; −17, −14 and +38%; and −24, −14 and +36%, respectively. There was a relationship between the changes in DBP and HR and plasma concentrations of nilvadipine only after dosing regimen 1. The effect‐concentration relationships were fit to a modified Emaxmodel. There was no relationship between the change in SBP and plasma concentration after any of the dosing regimens. While there were no significant differences in the mean area under the plasma concentration‐time curve (AUC0→∞) between dosing regimens 2 (38.7 ng ṁ hr/mL) and 3 (42.1 ng ṁ hr/mL) (P > 0.05), the mean AUC0→∞after regimen 1 (76.3 ng ṁ hr/mL) was significantly greater than after dosing regimens 2 or 3 (P < 0.05). The mean maximal plasma concentrations (Cmax) were 31.6, 1.3 and 6.3 ng/mL after dosing regimens 1, 2 and 3, respectively. Overall the results showed that nilvadipine caused changes in blood pressure and HR and that the largest changes were seen with dosing regimen 1, where peak plasma concentrations were greater than about 10 ng/mL.