Pharmacokinetics, Safety and Tolerability of Tylerdipine Hydrochloride, a Novel Dihydropyridine Dual L/T-type Calcium Channel Blocker, after Single and Multiple Oral Doses in Healthy Chinese Subjects.

Abstract

Tylerdipine hydrochloride (KBP-5660) is a novel L/T-type dual calcium channel blocker developed for thetreatment of hypertension. We aimed to study the pharmacokinetics, safety and tolerability of tylerdipine in healthy Chinese subjects. Two double-blind, randomized, dose-escalation studies were conducted that included a total of 88 healthy subjects: (1) a single-ascending dose (SAD) study; and (2) a multiple-ascending dose (MAD) study. In the SAD study, 64 subjects were randomly assigned to receive a single dose of 0.5, 2.5, 5, 10, 15, 20, 25, or 30mg of tylerdipine or placebo. In the MAD study, 24 subjects were randomly assigned to receive 10 or 20mg of tylerdipine or placebo once daily for 9days. Blood samples were collected at the designated time points for pharmacokinetic analyses. Safety assessments were conducted throughout the study. Following a single oral dose of tylerdipine of 5-30mg, the mean maximum plasma concentration (Cmax) increased from 0.9993 to 10.11ng/ml; mean area under the plasma-concentration curve (AUC) from time zero to 72h increased from 4.332 to 73.95h·ng/ml. AUC increased in a greater than dose-proportional manner, whereas Cmax exhibited a rough but non-typical dose-proportionality increase. In the MAD study, steady-state conditions were achieved after 1week of daily dosing in both dose groups. Accumulation of tylerdipine was low, with accumulation ratios (RAUC) of less than 1.65. All adverse events were assessed as mild or moderate. Tylerdipine hydrochloride was safe and well tolerated. The exposure (AUC) of tylerdipine over the dose range of 5-30mg increased in a greater than dose-proportional manner, while Cmax exhibited a rough but non-typical dose proportionality increase. A slight accumulation of tylerdipine was observed following multiple dosing. CTR20140862 and CTR20150660.