Vol.53 No.S-1 July 2005

Phase I study of doripenem, a new carbapenem antibiotic for injection in healthy volunteers

Mitsuyoshi Nakashima¹⁾ and Takayoshi Oguma²⁾

¹⁾Hamamatsu Institute of Clinical Pharmacology & Therapeutics, 40-3 Sukenobu-cho, Hamamatsu, Shizuoka, Japan
²⁾Developmental Research Laboratories, Shionogi & Co., Ltd.

Abstract

To evaluate the safety and pharmacokinetic profiles of doripenem (DRPM), a new carbapenem antibiotic for injection, we conducted a phase I study in 46 healthy male volunteers. DRPM was administered as follows: 1) a single infusion at a dose of 125-1,000 mg, 2) an infusion of 500 mg twice a day (1,000 mg/day) for 6 days (11 repeated infusions), 3) an infusion of 1,000 mg twice a day (2,000 mg/day) for 6 days (11 repeated infusions), and 4) an infusion of 500 mg 3 times a day (1,500 mg/day) for 1 day (3 repeated infusions).
In terms of safety, no abnormalities were found in the single-dose study. No abnormalities were found in electroencephalography or physical examination. In repeated dose studies, mild subjective symptoms/objective observations and slight changes in laboratory values were observed, although none were clinically relevant.
In the single-dose study, Cmax and AUC of DRPM increased in proportion to the dose, showing linearity between pharmacokinetic profiles and the DRPM dose. The plasma half-life of DRPM was approximately 1 hour at any dose. Within 24 hours of administration, approximately 75% of DRPM was excreted unchanged in urine. Results from the repeated-dose study showed that DRPM pharmacokinetic profiles were not affected by a repeated dose. In addition, DRPM was found not to be accumulated.
The mean serum protein binding ratio was 5.4-15.2%. Intestinal flora was slightly affected by DRPM administration.
This study showed that DRPM administration is safe up to a dose of 1,000 mg, and pharmacokinetic profiles are not affected by a repeated dose, with no DRPM accumulation.

Key word

carbapenem, doripenem, phase I clinical study, healthy volunteer

Received

January 11, 2005

Accepted

March 28, 2005

Jpn. J. Chemother. 53 (S-1): 104-123, 2005