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Levornidazole is the levo-isomer of ornidazole with similar anti-anaerobic activity and lower central neurotoxicity compared with ornidazole. This open-label, parallel, randomised, multidose trial was conducted to compare the pharmacokinetics and safety of levornidazole following intravenous (i.v.) infusion 750 mg every 24 h (q24h) (test group, 12 subjects) versus 500 mg every 12 h (q12h) (reference group, 12 subjects) for 7 days in healthy Chinese volunteers. Following i.v. infusion for 7 days, the test group showed a 33.8% lower accumulation ratio (AR) and a 45.0% higher volume of distribution of levornidazole than the reference group. The cumulative urinary excretion rate of levornidazole during the 0–72 h period (Ae 0–72 ) was 16.6 ± 20.9% in the test group and 24.2 ± 5.7% in the reference group. The metabolite M1/parent and M4/parent ratios were, respectively, 2.18 ± 0.77% and 2.94 ± 0.37% in test group and 3.15 ± 1.09% and 3.18 ± 0.34% in the reference group. The Ae 0–72 of M1, M2 and M4 were all <10% in both groups. Both regimens were well tolerated. Drug-related adverse events were generally transient and were mild or moderate in severity. These findings support the recommendation of i.v. infusion of levornidazole 750 mg q24h in clinical practice, which shows a lower AR and similar safety compared with the conventional 500 mg q12h regimen. [Chinese Clinical Trial Registry identifier: ChiCTR-IPR-14005574.] [ABSTRACT FROM AUTHOR]

Purpose Levornidazole, the levo-isomer of ornidazole, is a third-generation nitroimidazole derivative newly developed after metronidazole, tinidazole, and ornidazole. An open-label, parallel-controlled, single-dose study was conducted for the investigation of the pharmacokinetic (PK) profile of levornidazole and its metabolites in healthy elderly Chinese subjects, and for the evaluation of 2 dosing regimens in the elderly. Methods Levornidazole was intravenously administered at 500 mg to healthy elderly (aged 60–80 years) or young subjects (aged 19–45 years). The PK profiles of levornidazole and its metabolites in elderly subjects were evaluated and compared with those in the young group. WinNonlin software was used for simulating the PK profile of levornidazole in the elderly population following the dosing regimens of 500 mg BID and 750 mg once daily for 7 days. Monte Carlo simulation was used for estimating the cumulative fraction of response and probability of target attainment of both dosing regimens against Bacteroides spp. Results The C max , AUC 0–24, and AUC 0–∞ values of levornidazole in the elderly group were 11.98 μg/mL, 131.36 μg·h/mL, and 173.61 μg·h/mL, respectively. The t 1/2 , CL t , and mean residence time from time 0 to infinity were 12.21 hours, 2.91 L/h, and 16.46 hours. The metabolic ratios of metabolites (M) 1, 2, 4, and 6 were <3.0%, and that of M16 was 17.70%. The urinary excretion values of levornidazole, M1, M2, M4, M6, and M16 over 96 hours were 10.21%, 0.92%, ~0%, 2.69%, 0.54%, and 41.98%. The PK properties of levornidazole and the urinary excretion of all metabolites were not statistically different between the 2 groups. The cumulative fraction of response was >90% against B fragilis and other Bacteroides spp, and the probability of target attainment was >90% when the minimum inhibitory concentration was ≤1 μg/mL, in both groups. Implications No dosing regimen adjustment is suggested when levornidazole is used in elderly patients with normal hepatic functioning and mild renal dysfunction. The findings from the PK/PD analysis imply that both regimens may achieve satisfactory clinical and microbiological efficacy against anaerobic infections in elderly patients. Chinese Clinical Trial Registry ( http://www.chictr.org.cn ) identifier: ChiCTR-OPC-16007938. [ABSTRACT FROM AUTHOR]

Highlights: [•] We developed an UPLC–MS/MS method for simultaneous determination of levornidazole and its three metabolites M1, M2 and M4 in human plasma and urine. [•] The method is fully validated in terms of linearity, specificity, precision and accuracy, recovery and stability under various conditions. [•] The method is successfully applied in a clinical pharmacokinetic study. [ABSTRACT FROM AUTHOR]

Levornidazole is a novel third-generation nitroimidazoles antibiotic which metabolism and disposition in human are not well known. We have previously developed two methods to quantify levornidazole and its phase I metabolites, Ml (Hydroxylation metabolite), M2 (N-dealkylation metabolite) and M4 (Oxidative dechlorination metabolite), in human plasma and urine. In this study, we developed three novel liquid chromatographic-tandem mass spectrometric (LC-MS/MS) methods and analyzed its phase II metabolites, sulfate conjugate (M6) and glucuronide conjugate (M16), in human plasma and urine, and the parent drug and above-mentioned five metabolites in human feces samples. Analytes and internal standard (IS) in human plasma were extracted by a solid-phase extraction procedure and separated on an ACQUITY UPLC CSH C18 column in gradient elution using acetonitrile and 0.1% formic acid aqueous solution as the mobile phase. The pretreatment procedures for urine and feces homogenate samples involved a protein precipitation followed by liquid-liquid extraction, and chromatographic separations were performed on the Atlantis T3 columns of different lengths and particle sizes (2.1 × 50 mm, 3 μm and 2.1 × 150 mm, 5 μm), respectively. The mobile phases consisted of formic acid and acetonitrile-methanol solution (v/v, 50:50) in gradient elution. The MS/MS analysis was conducted on TSQ Quantum triple quadrupole mass spectrometer using electrospray ionization with selected reaction monitoring (SRM) in the positive ion mode. The calibration curves for all analytes were linear and the validation ranges were as follows: 0.005–0.500 μg/mL for M6 and 0.005–2.500 μg/mL for M16 in plasma; 0.010–10.000 μg/mL for M6 and M16 in urine; 0.005–1.000 μg/mL for levornidazole, M2, M4 and M16, and 0.010–2.000 μg/mL for M1 and M6 in human feces homogenate. Across these matrices, mean intra- and inter- batch accuracy values were in the ranges of 80.0%–120.0%, and intra- and inter-batch precision values did not exceed 20%. It was fully validated including selectivity, linearity, matrix effect, extraction recovery, stability, dilution integrity, carryover and incurred sample analysis (ISR). These newly developed methods were successfully applied in pharmacokinetics, metabolism and disposition study of levornidazole in 12 healthy Chinese subjects. [ABSTRACT FROM AUTHOR]

• The first population pharmacokinetic model of levornidazole in Chinese subjects was developed. • Pharmacokinetic/pharmacodynamic analysis of four sequential dosing regimens was performed. • Body weight was identified as a significant covariate of levornidazole clearance. • 750 mg q24h was proposed for patients against Bacteroides spp. (minimum inhibitory concentration ≤1 mg/L). Although sequential treatment with levornidazole 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. A 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 minimum inhibitory concentration (MIC) values 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 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 followed by 750 mg oral dose q24h for 5 days was optimal for Bacteroides spp. with an identified MIC ≤1 mg/L. [ABSTRACT FROM AUTHOR]