Pharmacodynamic evaluation of biapenem in peritoneal fluid using population pharmacokinetic modelling and Monte Carlo simulation

This study evaluated the pharmacodynamics of biapenem in peritoneal fluid (PF). Biapenem (300 or 600 mg) was administered via a 0.5-h infusion to 19 patients before abdominal surgery. Venous blood and PF samples were obtained after 0.5, 1, 2, 3, 4, 5 and 6 h. Drug concentration data (108 plasma samples and 105 PF samples) were analysed using population pharmacokinetic modelling. A three-compartment model fits the data, with creatinine clearance (CLCr) as the most significant covariate: CL (L/h) = 0.036 × CLCr + 4.88, V1 (L) = 6.95, Q2 (L/h) = 2.05, V2 (L) = 3.47, Q3 (L/h) = 13.7 and V3 (L) = 5.91, where CL is the clearance, Q2 and Q3 are the intercompartmental clearances, and V1, V2 and V3 are the volumes of distribution of the central, peripheral and peritoneal compartments, respectively. A Monte Carlo simulation using the pharmacokinetic model showed the probabilities of attaining the bactericidal exposure target (30% of the time above the minimum inhibitory concentration (T > MIC)) in PF were greater than or equal to those in plasma. In the cases of CLCr = 90 and 60 mL/min, the site-specific pharmacodynamic-derived breakpoints (the highest MIC values at which the probabilities of target attainment in PF were ≥90%) were 2 μg/mL for 300 mg every 12 h, 4 μg/mL for biapenem 300 mg every 8 h (q8h) and 8 μg/mL for 600 mg q8h. Thus, these results should support the clinical use of biapenem as a treatment for intra-abdominal infections and facilitate the design of the dosing regimen.