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

Although sequential treatment with levornidazole has been used for anaerobic infection in clinical prac-tice, 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. A population PK model was built us-ing 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 minimum inhibitory concentration (MIC) values of levornidazole against 375 anaerobic strains. Four se-quential dosing regimens (500 mg q12h, 1000 mg loading dose followed by 500 mg q12h, 750 mg q24h, and 10 0 0 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 described adequately by two-and one-compartment models, 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 the simulation results, patients' safety and compliance, levornidazole 750 mg intravenous infusion q24h for 2 days fol-lowed by 750 mg oral dose q24h for 5 days was optimal for Bacteroides spp. with an identified MIC <= 1 mg/L.(c) 2023 Published by Elsevier Ltd.

Automated summary

This study evaluated the pharmacokinetics of levornidazole in healthy subjects and patients, and proposed an evidence-based sequential dosing regimen. Monte Carlo simulation was used to evaluate four dosing regimens. The simulations showed that satisfactory treatment outcomes were achieved for all four regimens when the minimum inhibitory concentration (MIC) was less than or equal to 1 mg/L.