Pharmacokinetics, safety, and dose optimization of GST-HG171 in renal impairment: insights from physiologically based pharmacokinetic modeling

GST-HG171 is an orally administered inhibitor of the 3C-like protease that has been approved in China for the treatment of mild to moderate COVID-19. When co-administered with ritonavir, GST-HG171 is eliminated by the kidney. Therefore, this study evaluated the impact of renal impairment on its pharmacokinetics (PK), safety, and tolerability. A total of 24 participants were enrolled: 8 with normal renal function, 8 with mild renal impairment, and 8 with moderate renal impairment. Participants received 100 mg ritonavir at −12, 0, 12, and 24 h, with a single 150 mg dose of GST-HG171 co-administered at 0 h to maintain CYP3A inhibition. Compared with healthy subjects, mild renal impairment increased GST-HG171 exposure; the geometric least-squares mean ratios (90% confidence intervals) for C max , AUC 0 –t , and AUC 0–∞ were 118.15 (99.38–140.46), 139.48 (111.21–174.95), and 138.46 (111.19–172.42), respectively. Moderate impairment further increased exposure, with ratios of 131.81 (108.34–160.36), 186.18 (150.47–230.36), and 182.64 (148.03–225.33), respectively. Renal clearance was reduced by 22.7% and 52% in the mild and moderate impairment groups, respectively. GST-HG171 was generally tolerated across all groups, but adverse reactions related to hypertriglyceridemia should be monitored. Physiologically based PK modeling supported dose reductions for patients with renal impairment, recommending GST-HG171/ritonavir 100/100 mg twice daily for mild impairment and 50/100 mg twice daily for moderate impairment, administered for 5 days. CLINICAL TRIALS This study is registered with ClinicalTrials.gov as NCT06106126 .