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

• We developed a population pharmacokinetic model of biapenem in Chinese patients with lower respiratory tract infections (LRTIs).
• Creatinine clearance (CLCr) was found to be the most significant covariate affecting drug clearance.
• Biapenem 0.3 g every 12 h (0.5-h infusion) was insufficient to achieve satisfactory clinical outcomes in Chinese patients with LRTIs.
• Higher doses and longer infusion time of biapenem would be appropriate for pathogen bacteria with MIC ≥4 μg/mL.

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) × 0.049; Vc (L) = 13; Q (L/h) = 8.74; and Vp (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 μg/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 μg/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 μg/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.