Effects of Hepatic or Renal Impairment on Pharmacokinetics of Fruquintinib

Fruquintinib (FRUZAQLA^TM) is a highly selective tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors (-1, -2, and -3). Two Phase 1, open-label, single-dose studies investigated the impact of hepatic or renal impairment on the pharmacokinetics and tolerability of fruquintinib. Participants with moderate renal impairment (creatinine clearance [CrCl] 30-59 mL/min; eight participants) and matched healthy controls (eight participants for each study) received fruquintinib 5 mg. Participants with moderate hepatic impairment (Child–Pugh B; eight participants) and severe renal impairment (CrCl 15-29 mL/min; eight participants) received fruquintinib 2 mg. Pharmacokinetic samples were collected over 240 h. Fruquintinib pharmacokinetics were similar between participants with moderate hepatic impairment and healthy controls; geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for maximum plasma concentration (C_max), area under the plasma concentration–time curve from 0 to time of last measurable concentration (AUC_0-t), and AUC from 0 to infinity (AUC_0-inf) were 1.04 (0.87-1.24), 0.89 (0.64-1.23), and 0.91 (0.66-1.26), respectively. Fruquintinib pharmacokinetics were similar between participants with severe or moderate renal impairment and healthy controls. Compared with healthy controls, the respective GMRs (90% CIs) for C_max, AUC_0-t, and AUC_0-inf for participants with severe renal impairment were 0.89 (0.78-1.03), 0.97 (0.83-1.14), and 1.01 (0.85-1.19), and for participants with moderate renal impairment were 0.95 (0.78-1.15), 1.06 (0.89-1.26), and 1.07 (0.89-1.28). Fruquintinib was generally well tolerated. These results support fruquintinib use without dose adjustment (5 mg daily, 3 weeks on, and 1 week off) in patients with moderate hepatic impairment or moderate to severe renal impairment.