Population pharmacokinetics of meropenem-vaborbactam in acutely ill hospitalized patients with various degrees of renal dysfunction including continuous renal replacement therapy

Real-world meropenem-vaborbactam (MVB) pharmacokinetic-pharmacodynamic (PK/PD) attainment data in patients with renal dysfunction including continuous renal replacement (CRRT) are lacking. We evaluated MVB PK in patients with renal dysfunction and CRRT. Patients requiring hemodialysis were excluded. Plasma concentrations were quantified using LC-MS/MS. Multiple compartmental PK models and covariate effects were evaluated using Pmetrics 2.1.1. Free (f) fractions of 98% and 67% were assumed with targets of 40%- 100% fT_>MIC and fAUC/MIC >38 for meropenem (MEM) and vaborbactam (VAB), respectively. Individual patient PK/PD attainment was evaluated using Bayesian posterior predictions. Probability of target attainment (PTA) stratified by MIC and cumulative fraction of response (CFR) vs the EUCAST K. pneumoniae distribution were evaluated for 2 and 4 g MVB regimens. Eighteen patients (54% female, 17% CRRT) aged 54 ± 14 years, weighing 91 ± 31 kg with a CrCL of 114 ± 102 mL/min/1.73 m² at baseline, contributed 83 plasma samples. For each drug, a one-compartment PK model was identified. Non-CRRT and residual clearance of MEM was higher than VAB, resulting in VAB accumulation. Individual-patient target attainment was variable. MEM PTA was >90% at MICs up to 0.5 mg/L, and VAB PTA was >90% at MICs up to 4 mg/L across renal states. CFR for MEM was >80%, and CFR for VAB was >70% in patients with renal dysfunction or CRRT and standard PK/PD targets with renal dosing regimens. For infections with MICs up to 1 mg/L, MVB regimens of 2 g IV every 8 h were adequate in CRRT. Studies linking MVB attainment to clinical outcomes are needed.