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
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Background and Objective
Tylerdipine hydrochloride (KBP-5660) is a novel L/T-type dual calcium channel blocker developed for the treatment 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 30 mg of tylerdipine or placebo. In the MAD study, 24 subjects were randomly assigned to receive 10 or 20 mg of tylerdipine or placebo once daily for 9 days. 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 5–30 mg, the mean maximum plasma concentration (Cmax) increased from 0.9993 to 10.11 ng/ml; mean area under the plasma-concentration curve (AUC) from time zero to 72 h increased from 4.332 to 73.95 h·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 1 week 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 5–30 mg 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.
The authors thank all the subjects who participated in the studies. This work was supported by the XuanZhu Pharma Co., Ltd. (Jinan, China).
Compliance with Ethical Standards
This study was funded by Xuan Zhu Pharma Co., Ltd. (Jinan, China).
Conflict of interest
The authors have no potential conflicts of interest to report.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The studies were approved by the Ethics Committee of the First Affiliated Hospital with Nanjing Medical University (Nanjing, China) and the approval numbers are 2014-MD-164.A1 for SAD study and 2015-MD-141 for MAD study, respectively.
Informed consent was obtained from all individual participants included in the study.
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