Population pharmacokinetics of levornidazole in healthy subjects and patients and sequential dosing regimen proposal using pharmacokinetic/pharmacodynamic analysis.

Abstract

Although levornidazole sequential treatment has been used for anaerobic infection in clinical practice, there is no evidence-based dosing regimen. This study aimed to evaluate the pharmacokinetics (PK) of levornidazole in healthy subjects and patients and to propose an evidence-based sequential dosing regimen by pharmacokinetic/pharmacodynamic (PK/PD) analysis. Population PK model was built using the data of 116 Chinese subjects, including 88 healthy young subjects, 12 healthy elderly subjects, and 16 patients with intra-abdominal anaerobic infection. PK/PD analysis was performed combining the minimuminhibitoryconcentrations (MICs) of levornidazole against 375 anaerobic strains. Four sequential dosing regimens (500 mg q12h, 1000 mg loading dose followed by 500 mg q12h, 750 mg q24h, and 1000 mg q24h) were evaluated in terms of cumulative fraction of response (CFR) and probability of target attainment (PTA) by Monte Carlo simulation. The concentration data of levornidazole and its active metabolites were adequately described by two- and one-compartment model, respectively. Body weight was identified as a significant covariate of levornidazole clearance. Simulations showed that satisfactory PTA (> 90%) was achieved for the four dosing regimens when MIC ≤ 1 mg/L. Considering simulation results, patients' safety and compliance, levornidazole 750 mg IV infusion q24h for 2 days followed by oral dose of 750 mg q24h for 5 days was optimal for Bacteroides spp. with an identified MIC ≤ 1 mg/L.