Clinical Pharmacokinetics of Levornidazole in Elderly Subjects and Dosing Regimen Evaluation Using Pharmacokinetic/Pharmacodynamic Analysis

• Published in: Clinical therapeutics 2017-07, Vol.39 (7), p.1336-1346
• Main Authors: Guo, Beining, PhD, He, Gaoli, MS, Wu, Xiaojie, PhD, Yu, Jicheng, BS, Cao, Guoying, MS, Li, Yi, MS, Fan, Yaxin, MS, Chen, Yuancheng, PhD, Shi, Yaoguo, BS, Zhang, Yingyuan, BS, Zhang, Jing, PhD
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Anti-Infective Agents - blood; Anti-Infective Agents - pharmacokinetics; Anti-Infective Agents - pharmacology; Anti-Infective Agents - urine; Bacteria; Bacteroides - drug effects; Bacteroides - growth & development; Computer programs; Computer simulation; Dosage; dosing regimen evaluation; Drug dosages; Drug therapy; elderly subject; Evaluation; Excretion; Female; Geriatrics; Humans; Infinity; Internal Medicine; Kinetics; levornidazole; Male; Medical Education; Metabolism; metabolite; Metabolites; Metronidazole; Microbial Sensitivity Tests; Middle Aged; Minimum inhibitory concentration; Models, Biological; Monte Carlo Method; Monte Carlo simulation; Nitroimidazole; Older people; Ornidazole; Ornidazole - blood; Ornidazole - pharmacokinetics; Ornidazole - pharmacology; Ornidazole - urine; Participation; Patients; Pharmacodynamics; Pharmacokinetics; Pharmacology; Renal function; Simulation; Software; Tinidazole; Urine; Young Adult
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2017.05.350

Abstract 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 Cmax , AUC0–24, and AUC0–∞ 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 t1/2 , CLt , 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 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.