Evaluation of the Pharmacokinetics and Renal Excretion of Simeprevir in Subjects with Renal Impairment

Background Simeprevir is a N3/4 protease inhibitor approved for the treatment of hepatitis C virus (HCV) infection. HCV prevalence is higher in patients with chronic kidney disease compared with the general population; safe and efficacious therapies in renal impairment are needed. Objectives To evaluate simeprevir renal excretion in healthy subjects and to compare the simeprevir steady-state pharmacokinetics between subjects with severe renal impairment and healthy subjects. Methods In the mass balance study, healthy adults received a single 200-mg dose of 14 C-simeprevir; radioactivity in the urine and feces was quantified until concentrations were <2 % of the administered dose and seven or more stools were produced. In the pharmacokinetic study, non-HCV-infected adults with severe renal impairment (estimated glomerular filtration rate ≤29 mL/min/1.73 m 2 ) and matched healthy subjects (estimated glomerular filtration rate ≥80 mL/min/1.73 m 2 ) received 150 mg simeprevir for 7 days. Pharmacokinetic analysis was performed post-dose on Day 7. Results 14 C-simeprevir recovery from the urine was low (0.009–0.138 % of total dose). The minimum plasma concentration, maximum plasma concentration, and area under the plasma concentration-time curve at 24 h were 71, 34, and 62 % higher, respectively, in subjects with severe renal impairment compared with healthy subjects. The mean fraction of simeprevir unbound to protein was <0.0001 (all subjects). Most adverse events were grade I or II; one subject with renal impairment who was receiving fenofibrate presented with grade 3 rhabdomyolysis. Conclusions Simeprevir plasma concentrations were mildly elevated in subjects with severe renal impairment. The results suggest that simeprevir may be administered without dose adjustment in patients with renal impairment.