Vol.68 No.S-1 November 2020
Pharmacokinetics of lascufloxacin in patients with renal dysfunction
1)Department of Urology, University of Occupational and Environmental Health
2)Seijinkai Ikeda Hospital
3)Kawahara Clinic
4)Clinical Research Hospital Tokyo
(Past: CPC Clinical Trial Hospital, Medipolis Medical Research Institute)
5)Watarase Research Center, Kyorin Pharmaceutical Co., LTD.
Abstract
To obtain reference data for dose adjustment of lascufloxacin (LSFX) in patients with specific backgrounds, the effects of renal function impairment on the pharmacokinetics (PK) and safety of LSFX were investigated in Japanese male and female volunteers with normal renal function or mildly/moderately/severely impaired renal function. After a single oral administration of 75 mg LSFX to five or six subjects in each group, PK analyses were performed by measuring the plasma concentrations and urinary excretion levels of LSFX and its main metabolite, the descyclopropyl form.
The plasma concentrations of LSFX in the subjects with impaired renal function were almost the same as those in the subjects with normal renal function, regardless of the severity of the renal function impairment. While the renal clearances (CLr) of LSFX tended to decrease with increasing degree of renal function impairment (0.581, 0.412, 0.229 and 0.249 L/h in subjects with normal renal function and those with mildly, moderately, and severely impaired renal function, respectively), no such trend was apparent in the mean areas under the curve (AUClast), mean total clearance, mean volume of distribution, or mean elimination half-life (t1/2); the t1/2 values also remained almost constant in the range of 16.0 hours to 17.9 hours. The plasma concentrations of the descyclopropyl form of the drug were maintained at 1/5th to 1/10th of those of LSFX. The CLr AUClast values of the descyclopropyl form decreased and increased, respectively, as follows, with increasing degree of renal function impairment (10.7, 5.36, 3.62 and 1.97 L/h, and 1.86, 3.67, 4.04 and 4.95 μg・h/mL, respectively in subjects with normal renal function and those with mildly, moderately, and severely impaired renal function). While there was no significant difference in the t1/2 value in patients with mild and moderate renal function impairment as compared to that in those with normal renal function, the t1/2 showed a 1.6-fold increase in patients with severe renal function impairment as compared to that in subjects with normal renal function (19.1, 20.5, 22.7, and 30.3 hours, respectively, in subjects with normal renal function and those with mildly, moderately, and severely impaired renal function). The urinary excretion of LSFX until 72 hours after the dosing in subjects with normal renal function and those with mildly, moderately, and severely impaired renal function were 10.5%, 8.90%, 3.63%, and 3.59%, and the corresponding values for the descyclopropyl form were 28.5%, 28.2%, 22.5%, and 13.5%, respectively. As shown by these results, the urinary excretion rates were decreased in both patients with moderately and severely impaired renal function.
There were neither adverse events related to the investigational drug, nor abnormal changes or findings in the clinical laboratory values, vital signs or ECG in the subjects with renal impairment of any severity.
Based on the results of this study, we report that the effect of renal function impairment on the PK of LSFX is small enough to preclude the need for any dose adjustment depending on the degree of in patients with renal function impairment.
Key word
lascufloxacin, renal dysfunction, pharmacokinetics, clinical trial
Received
October 30, 2019
Accepted
June 16, 2020
Jpn. J. Chemother. 68 (S-1): 16-23, 2020
