Pharmacokinetics and Pharmacodynamics of Levornidazole in Patients With Intra-abdominal AnaerobicInfection

Purpose: The pharmacokinetic (PK) and pharmacodynamic characteristics of levornidazole were studied in patients with intra-abdominal anaerobic infection to provide the rationale of new clinical dosing regimen of levornidazole.

Methods: A single-center, open, multidose trial was conducted in 16 patients with intra-abdominal anaerobic infection. Patients received levornidazole at 500mg q12h by intravenous infusion for 3 to 7days. The plasma samples collected before and after the last dose were analyzed by the LC-MS/MS method to determine the concentration of levornidazole. The PK parameters of levornidazole were calculated, and the PK profiles of levornidazole after the dosing regimen of 750mg q24h for 7days were simulated based on the linear PK profile of levornidazole. Monte Carlo simulation was used for estimating the cumulative fraction of response and probability of target attainment (PTA) of both dosing regimens at steady-state against Bacteroides fragilis.

Findings: After administration of the last dose of 500mg of levornidazole, the mean (SD) C_{max_ss}, AUC_0-12, and t_1/2 of levornidazole were 24.0 (5.37) μg/mL, 176.59 (29.22) μg·h/mL, and 11.03 (1.34) hours, respectively. The mean (SD) CL_ss and V_ss of levornidazole were 2.90 (0.47) L/h and 45.90 (7.44) L, respectively. The mean (SD) distribution volume of central compartment (V1) and distribution volume of peripheral compartment (V2) were 26.71 (8.51) L and 19.21 (10.86) L, respectively. On the basis of simulation, the accumulation ratio of levornidazole in the 750mg q24h dosing regimen was 30.2% lower than the value in the 500mg q12h dosing regimen. Forthe 2 dosing regimens, the C_{max_ss}, AUC_0-τ, AUC_0-∞, CL_ss, and V_ss did not produce a significant difference between patients and healthy volunteers (P > 0.05). The cumulative fraction of response of levornidazole against B fragilis was >90%, and the probability of target attainment after both dosing regimens was >90%, when the MIC was ≤1 μg/mL.

Implications: No significant differences were found in the PK profiles of levornidazole at steady state between the patients with intra-abdominal anaerobic infection and healthy volunteers. The clinical conventional 750mg q24h regimen can achieve similar clinical and microbiological efficacies against anaerobic in the patients after the 500mg q12h regimen.