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

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 <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.

Quantification of levornidazole and its metabolites in human plasma and urine by ultra-performance liquid chromatography-mass spectrometry.

We developed and validated an ultra-performance liquid chromatographic (UPLC) method coupled with atmospheric pressure chemical ionization (APCI) mass spectrometry for simultaneous determination of levornidazole and its first-pass metabolites, l-chloro-3-(2-hydroxymethyl-5-nitro-l-imidazolyl)-2-propanol (Ml), 2-methyl-5-nitroimidazole (M2) and 3-(2-methyl-5-nitro-1-imidazolyl)-1,2-propanediol (M4), in human plasma and urine. The biological samples were pretreated by protein precipitation and liquid-liquid extraction and analyzed using an ACQUITY UPLC CSH C18 column (2.1×50 mm, 1.7 µm) and a QTRAP mass spectrometer in multiple reaction monitoring mode via APCI. Acetonitrile and 0.1% formic acid in water was used as the mobile phase in gradient elution at a flow rate of 0.6 mL/min. The lower limit of quantification of this method was 0.0100, 0.00500, 0.0200 and 0.00250 µg/mL for levornidazole, M1, M2 and M4, respectively. The linear calibration curves were obtained for levornidazole, M1, M2, and M4 over the range of 0.0100-5.00, 0.00500-2.50, 0.0200-10.0 and 0.00250-1.25 µg/mL, respectively. The intra- and inter-batch precision was less than 12.2% in plasma and less than 10.8% in urine. The intra- and inter-batch accuracy was 87.8-105.7% in plasma and 92.8-109.2% in urine. The mean recovery of levornidazole, M1, M2 and M4 was 91.1-105.1%, 95.8-103.8%, 87.8-96.8%, 96.8-100.6% from plasma and 96.0-100.9%, 96.9-107.9%, 95.1-102.7%, 103.7-105.9% from urine respectively. This method was validated under various conditions, including room temperature, freeze-thaw cycles, long-term storage at -40 ± 5°C, after pretreatment in the autosampler (at 10°C), and 10- and 100-fold dilution. This newly established analytical method was successfully applied in a pharmacokinetic study following single intravenous infusion of levornidazole in 24 healthy Chinese subjects.

The effect of (R,S)-ornidazole on the fertility of male mice and the excretion and metabolism of 36Cl-(R,S)-ornidazole and 36Cl-(R,S)-alpha-chlorohydrin in male mice and rats.

(R,S)-Ornidazole, an effective antifertility agent for male rats at 400 mg/kg/day, was ineffective at this dose in male mice and at 1000 mg/kg/day caused neural effects. The compound was not excreted unchanged and more polar metabolites and Cl- were detected in 0-8 h urine following a single injection (400 mg/kg). In 8-24 h urine even these metabolites and most Cl ion were absent, indicating rapid metabolism of ornidazole. There was no organ specific accumulation of 36Cl-(R,S)-ornidazole in murine tissues. After injection of 36Cl-(R,S)-alpha-chlorohydrin, another antifertility agent in the rat but not the mouse, there was also no tissue-specific accumulation of radioactivity in the reproductive tract of either species. Urinary excretion rates of alpha-chlorohydrin were twice as rapid in mice as in rats. In mice, alpha-chlorohydrin was the major urinary metabolite, but in the rat metabolites included Cl-, 3-chlorolactate (BCLA) at 5 and 10 h and BCLA only at 24 h. BCLA was the major metabolite detected in most tissues at 10 and 24 h. In the rat cauda (but not caput) epididymidis the glycolytic inhibitor 3-chlorolactaldehyde was present at 5 h (but not 10 h), indicative of early metabolism. These results demonstrate a greater metabolism and excretion of putative antifertility agents in the mouse than the rat, lowering the amount of effective inhibitor circulating in the animal, which may explain why (R,S)-alpha-chlorohydrin and (R,S)-ornidazole are ineffective in this species at the dosages and injection times used, despite their spermatozoa being sensitive to inhibition by (R,S)-alpha-chlorohydrin in vitro.

[Study of gastric elimination of ornidazole after intravenous administration in patients undergoing digestive surgery]. / Etude de l'élimination gastrique de l'ornidazole après administration intraveineuse chez des patients en chirurgie digestive.

In a previous study, performed in patients undergoing gastrointestinal surgery receiving antibiotics intravenously we pointed out that the gastric aspiration was an additional route of elimination for some drugs. In order to estimate the extra-dose required to replace losses in patients receiving ornidazole, a study was set up. 8 patients entered the trial; the patients were infused 500 mg of ornidazole for 3 days every 12 hours. Blood was sampled at 0-2-4-8-24 h after the last infusion. Urines and gastric aspirate were collected. The results indicate that the amount aspirated through the tubings is 69.1 +/- 37.5 mg per 24 hours (24.8 - 116.8) with a very high variability; the half-life was not different of what is known for ornidazole: 10.5 +/- 1.7 h. The results confirm that for the molecules weakly bound to protein which "concentrate" in the gastric secretion, the aspiration is an important route of elimination.

High haemodialysis clearance of ornidazole in the presence of a negligible renal clearance.

The pharmacokinetics of ornidazole was studied in 6 patients treated by haemodialysis and in 8 subjects with a creatinine clearance between 4 and 99 ml/min x 1.73 m2. Blood and urine collections were performed for 72 h after i.v. and oral administration of 1.0 g ornidazole. Total body clearance, half-life, volume of distribution and systemic availability were independent of renal function and did not differ from previously reported values in normal volunteers. The haemodialysis clearance of ornidazole was greater than 100% higher than the total body clearance. The renal clearance of ornidazole accounted for less than 7% of the total body clearance. The percentage of the dose of ornidazole recovered in urine as parent compound or as the biologically active metabolites [alpha-(chloromethyl)-2 hydroxymethyl-5 nitroimidazole-1 ethanol and 3-(2 methyl-5 nitroimidazole-1-yl)1,2 propanediol] decreased linearly with decreasing renal function. Although the sum of those three compounds recovered in urine accounted for less than 10% of the total dose of ornidazole administered, they yielded therapeutic concentrations (greater than 4 micrograms/ml) in urine over 24 h after dosing. Due to the peculiar pharmacokinetic behaviour of ornidazole, i.e. high haemodialysis clearance in the absence of significant renal clearance, no dosage adjustment is necessary while renal function declines, but an increased dose is mandatory while patients are on dialysis.

Metabolic studies of ornidazole in the rat, in the dog and in man.

1. Ornidazole, labelled with 14C in the imidazole ring, administered orally to rats, dogs and men was largely excreted in the urine, predominantly as metabolites, with less than 4% of the drug being excreted unchanged. Free and conjugated metabolites were found in the ratio of approx. 1 : 2. 2. The pattern of free ornidazole and metabolites was different in the three species: while ornidazole predominated in man, ornidazole and metabolite M1 in the dog, the most extensive metabolic pattern was found in the rat. 3. The following metabolites were identified: M1, 1-chlorlo-3-(2-hydroxymethyl-5-nitro-1-imidazolyl)-2-propanol; M2, 2-methyl-5-nitroimidazole; M3, N-(3-chloro-2-hydroxypropyl)acetamide: M4, 3-(-2-methyl-5-nitro-1-imidazolyl)-1, 2-propanediol; M5, acetamide. 4. The formation of metabolite M3 and M5 indicated cleavage of the imidazole ring between N-1/C-5 and C-2/C-3. Other ring scissions were not observed. Metabolites carrying a free amino group were not detected. On the basis of the structures identified, a scheme is suggested for the metabolism of ornidazole.