Optimal dosing regimen of biapenem in Chinese patients with lower respiratory tract infections based on population pharmacokinetic/pharmacodynamic modelling and Monte Carlo simulation

In this study, a population pharmacokinetic (PPK) model of biapenem in Chinese patients with lower respiratory tract infections (LRTIs) was developed and optimal dosage regimens based on Monte Carlo simulation were proposed. A total of 297 plasma samples from 124 Chinese patients were assayed chromatographically in a prospective, single-centre, open-label study, and pharmacokinetic parameters were analysed using NONMEN. Creatinine clearance (CLCr) was found to be the most significant covariate affecting drug clearance. The final PPK model was: CL (L/h) = 9.89 +(CLCr - 66.56) x 0.049; V-c (L) = 13; Q (L/h) = 8.74; and V-p (L) = 4.09. Monte Carlo simulation indicated that for a target of >= 40% T->MIC (duration that the plasma level exceeds the causative pathogen's MIC), the biapenem pharmacokinetic/pharmacodynamic (PK/PD) breakpoint was 4 mu g/mL for doses of 0.3 g every 6 h (3-h infusion) and 1.2 g (24-h continuous infusion). For a target of >= 80% T->MIC, the PK/PD breakpoint was 4 mu g/mL for a dose of 1.2 g (24-h continuous infusion). The probability of target attainment (PTA) could not achieve >90% at the usual biapenem dosage regimen (0.3 g every 12 h, 0.5-h infusion) when the MIC of the pathogenic bacteria was 4 mu g/mL, which most likely resulted in unsatisfactory clinical outcomes in Chinese patients with LRTIs. Higher doses and longer infusion time would be appropriate for empirical therapy. When the patient's symptoms indicated a strong suspicion of Pseudomonas aeruginosa or Acinetobacter baumannii infection, it may be more appropriate for combination therapy with other antibacterial agents. (C) 2016 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.