A First-in-Human Safety, Tolerability, and Pharmacokinetics Study of Benapenem in Healthy Chinese Volunteers

Abstract

The objective of this trial was to investigate the safety, tolerability, and pharmacokinetics (PK) of benapenem administered by single or multiple intravenous infusions in healthy Chinese volunteers. The trial was divided into 3 parts. In part A, 94 subjects were enrolled in a double-blind, placebo-controlled, sequential-ascending-single-dose study. The subjects were randomly assigned to groups receiving placebo or benapenem for injection at doses of 62.5, 125, 250, 500, 1,000, 2,000, or 3,000 mg. The effects of intravenous infusion time on the subjects of 250-, 500-, and 1,000-mg groups were explored. In part B, 12 subjects were enrolled in a single-dose PK study under fasting conditions and received 250, 500, or 1,000 mg of benapenem for injection. In part C, 36 subjects were given 250, 500, and 1,000 mg of benapenem for injection once daily for 7 consecutive days. The results showed that benapenem for injection was well tolerated during the studies. The major observed adverse events were mild, and all were resolved spontaneously without any medical intervention. Benapenem was mainly excreted through the kidneys in the form of parent molecule and metabolites. The PK and safety profiles of benapenem in healthy Chinese volunteers support its once-daily dosing in future clinical investigations. (Part A, part B, and part C have been registered at ClinicalTrials.gov under identifiers NCT03588156, NCT03578588, and NCT03570970, respectively.).

Keywords: benapenem; healthy Chinese volunteers; multiple dose; pharmacokinetics; safety; single dose; tolerance.

Copyright © 2019 American Society for Microbiology.

Figures

FIG 1

Chemical structure of benapenem and KBP-3331.

FIG 2

Mean plasma concentration-versus-time profiles of benapenem following a single dose or 7 days of multiple doses. (A and B) Two hundred fifty mg, 500 mg, and 1,000 mg benapenem in single-ascending-dose study, representing part B of the study. Panel A is linear scale, and panel B is log10 scale. (C and D) Two hundred fifty mg, 500 mg, and 1,000 mg benapenem in multiple-ascending-dose study, representing part C of the study. Panel C is linear scale, and panel D is log10 scale.

FIG 3

Mean accumulated amount of benapenem excreted in 48 h following a single dose.

FIG 4

Phase I trial design of benapenem in healthy Chinese volunteers. Part A, a single-ascending-dose study to assess safety and tolerability of benapenem; part B, a single-dose study to evaluate the PK profiles of benapenem and its major metabolites; part C, a multiple-dose study to assess the tolerability and PK profiles of benapenem and its major metabolites.