Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic derived dose justification for phase 3 studies in patients with nosocomial pneumonia.

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Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic derived dose justification for phase 3 studies in patients with nosocomial pneumonia.

J Clin Pharmacol. 2015 Jun 10;

Authors: Xiao AJ, Miller BW, Huntington JA, Nicolau DP

Abstract
Ceftolozane/tazobactam is an antipseudomonal antibacterial approved for treatment of complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI) and in Phase 3 clinical development for treatment of nosocomial pneumonia. A population pharmacokinetic (PK) model with the plasma-to-epithelial lining fluid (ELF) kinetics of ceftolozane/tazobactam was used to justify dosing regimens for patients with nosocomial pneumonia in phase 3 studies. Monte Carlo simulations were performed to determine ceftolozane/tazobactam dosing regimens with a >90% probability of target attainment (PTA) for a range of pharmacokinetic/pharmacodynamic targets at relevant minimum inhibitory concentrations (MICs) for key pathogens in nosocomial pneumonia. With a plasma-to-ELF penetration ratio of approximately 50% as observed from an ELF PK study, a doubling of the current dose regimens for different renal functions that are approved for cUTI and cIAI is needed to achieve >90% PTA for nosocomial pneumonia. For example, a 3 g dose of ceftolozane/tazobactam for nosocomial pneumonia patients with normal renal function is needed to achieve a >90% PTA (actual 98%) for the 1-log kill target against pathogens with an MIC of ≤8 mg/L in ELF, as compared to the 1.5-g dose approved for cIAI and cUTI.

PMID: 26096377 [PubMed - as supplied by publisher]