Pharmacokinetic/pharmacodynamic modeling and simulation to determine effective dosage regimens for doripenem.
The aim of this study was to obtain information on effective dosage regimens of doripenem by a modeling and simulation approach based on pharmacokinetic (PK)/pharmacodynamic (PD) theory. The PK/PD model we have already developed was modified to explain in vitro bactericidal kinetics of doripenem for several Pseudomonas aeruginosa strains. Time-course profiles of bacterial counts in patients infected with P. aeruginosa were simulated for typical clinical dosage regimens in Japan considering the variability of PK and the patients' backgrounds by a Monte Carlo simulation. Moreover, time-course profiles of probability achieving the criterion (log(CFU/mL) < 0) were predicted for the evaluation of antibacterial efficacy by renal function. The in vitro bacterial profiles at various dosage regimens could be well explained by the PK/PD model. The simulations suggested the dependence of antibacterial efficacy on the frequency of administration, indicating time-dependent antibacterial activity. It was also suggested that 500 mg t.i.d. showed significant bacterial reduction in patients for any degree of renal function and any severities in 2 weeks after the start of treatment. Our approach to simulate time-course profiles of bacterial counts should be useful for determining and examining effective dosage regimens, including the treatment period, in drug development.
Katsube
Takayuki
T
Clinical Research Department, Shionogi & Co., Ltd, Sagisu 5-12-4, Fukushima-ku, Osaka 553-0002, Japan. takayuki.katsube@shionogi.co.jp
Yano
Yoshitaka
Y
Wajima
Toshihiro
T
Yamano
Yoshinori
Y
Takano
Mikihisa
M
D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D015780:Carbapenems / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D003198:Computer Simulation; D000077726:Doripenem; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009010:Monte Carlo Method; D011550:Pseudomonas aeruginosa / Q000187:drug effects
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D000077726:Doripenem