Back to Search Start Over

Pharmacokinetics and Safety of Doripenem in Healthy Chinese Subjects and Monte Carlo Dosing Simulations

Authors :
Yu Wang
Xiaofen Liu
Kun Li
Yaxin Fan
Jicheng Yu
Hailan Wu
Yi Li
Xiaojie Wu
Beining Guo
Xin Li
Jiali Hu
Jufang Wu
Guoying Cao
Jing Zhang
Source :
Antibiotics, Vol 11, Iss 7, p 958 (2022)
Publication Year :
2022
Publisher :
MDPI AG, 2022.

Abstract

The aim of this study was to investigate the pharmacokinetics (PK) of doripenem in healthy Chinese subjects and evaluate the optimal dosage regimens of doripenem. A randomized, single-dose, three-period, self-crossover controlled extended-infusion clinical trial was conducted with 12 healthy Chinese subjects. Plasma and urine samples were collected to determine doripenem concentrations. Non-compartmental and population PK analysis were performed to characterize the PK of doripenem. The Monte Carlo simulation was employed to optimize dosing regimens based on the probability of target attainment of doripenem against pathogens with different minimum inhibitory concentrations (MIC). All 12 healthy Chinese subjects completed the study, and the doripenem was well tolerated. The study showed linearity relationships in the peak plasma concentration and the area under the concentration-time curve after intravenous infusion of doripenem from 0.25 g to 1.0 g. The cumulative urinary recovery rate of doripenem was 68.1–72.0% within 24 h. PPK modeling showed a two-compartmental model, with first-order elimination presenting the best fit for doripenem PK. Monte Carlo simulation results showed that 1.0 g q12h or 0.5 g q8h was an optimal regimen for pathogens susceptible to doripenem (MIC ≤ 1 mg/L); while high dose and extended infusion (1 g, q8h, 4 h infusion) was proposed for unsusceptible pathogens (2 ≤ MIC ≤ 8 mg/L). In the dose range of 0.25 to 1.0 g, doripenem showed linear pharmacokinetics. Doripenem at 1.0 g with a prolonged infusion time of 4 h was predicted to be effective against pathogens with MICs as high as 8 mg/L.

Details

Language :
English
ISSN :
20796382
Volume :
11
Issue :
7
Database :
Directory of Open Access Journals
Journal :
Antibiotics
Publication Type :
Academic Journal
Accession number :
edsdoj.f64607f76b0d4a4d8950951ca5619fbd
Document Type :
article
Full Text :
https://doi.org/10.3390/antibiotics11070958