title: Pharmacokinetic-pharmacodynamic modeling to support doripenem dose regimen optimization for critically ill patients.
abstract: Dose regimen selection in late-phase clinical trials is critical for successful drug development, the well-being of individual patients, and given the ongoing emergence of antimicrobial resistance, society as a whole. Herein we describe some of the animal pharmacokinetics-pharmacodynamics, human pharmacokinetic, and in silico modeling work that was conducted in an effort to maximize the probability of a positive clinical response to therapy and minimize the likelihood for exposure-related toxicity for doripenem in phase 3 clinical studies. Some of the dosing regimens identified have been validated as effective in phase 3 clinical studies (500 mg infused over 1 h every 8 h for complicated intra-abdominal infections), whereas others (1000 mg infused over 4 h every 8 h for hospital-acquired pneumonia) are undergoing clinical evaluation.
authors.affiliation: Institute for Clinical Pharmacodynamics, Ordway Research Institute, Latham, NY 12110, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Van Wart
authors.forename: David R
authors.initials: DR
authors.lastname: Andes
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ambrose
authors.forename: Sujata M
authors.initials: SM
authors.lastname: Bhavnani
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001424:Bacterial Infections / Q000188:drug therapy*; D015780:Carbapenems / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002986:Clinical Trials as Topic; D003198:Computer Simulation; D016638:Critical Illness; D000077726:Doripenem; D005260:Female; D006801:Humans; D051379:Mice
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D000077726:Doripenem