Clinical study of the pharmacokinetics and pharmacodynamics of Xininurad tablets in patients with renal impairment

The purpose of this trial was to evaluate the pharmacokinetics, pharmacodynamic characteristics and safety of a single fast oral administration of Xininurad tablets in subjects with different degrees of impaired renal function. A parallel, open, single-dose study design was adopted. To this end, 22 patients with varying degrees of renal function impairment were recruited for the study and classified into three groups based on their renal function status (eGFR): a normal renal function group consisting of nine patients, a group of patients with mild renal function impairment including eight patients and a group of patients with moderate renal function impairment involving five patients. The plasma and urine concentrations of Xininurad were measured by liquid-phase tandem mass spectrometry (LC-MS/MS), and changes in creatinine and uric acid levels were also monitored. The pharmacokinetic parameters were calculated using WinNonlin 7.0, which is a noncompartmental model, and the results were statistically analysed using SAS 9.4. After a single oral dose of 1 mg of Xininurad was administered as a tablet in the fasting state, the plasma level of Xininurad was slightly greater in the group with mild renal dysfunction than in the normal renal function group and the group with moderate renal dysfunction. The geometric mean Cmax (ng/mL) and AUC0-∞ (h·ng/ml) values in the normal renal function group, the group with mild renal dysfunction and the group with moderate renal dysfunction were 42.9, 57.7 and 46.0, and 982, 1380 and 1050, respectively; the percentage of free Xininurad in plasma was similar, ranging from 0.702% to 0.861%. The geometric means of the cumulative excretion ratios of Xininurad in urine (fe0-96h) were 0.723, 0.809 and 0.502%, suggesting that Xininurad is mainly excreted nonproportionally in urine or metabolized by the liver. The changes in serum uric acid relative to the baseline (MCFBUA) and the concentration-time area under the curve relative to the baseline (△AUEC0-24h) after Xininurad administration were similar in all groups, but the values of %MPUA and %AUEC0-24h relative to the baseline were slightly greater in the group with moderate renal dysfunction (the average %MPUA and %AUEC0-24h in the normal renal function, mild renal dysfunction and moderate renal dysfunction groups were -67.4, -63.6 and -48.8; %AUEC0-24h, and -50.2, -49.3 and -31.1, respectively). The reported adverse events and adverse reactions were all grade 1 in severity, and the outcomes were all recovery and remission. Mild or moderate renal function impairment had a limited influence on the pharmacokinetic characteristics of Xininurad. The serum uric acid level was noticeably lower in all the groups after drug administration. Compared with the normal group, moderate renal function impairment may have slightly reduced the uric-lowering effect of Xininurad, but the reduction range was not clinically significant, whereas mild renal function impairment had no effect. Safety and tolerability were good in all the subjects and abnormal renal function was not found to increase safety risk. This clinical trial is registered at http://www.chinadrugtrials.org.cn/clinicaltrials.searchlist.dhtml. CTR20211343, registration time:08/06/2021.