Renal impairment

The pharmacokinetics of sofosbuvir were studied in HCV negative subjects with mild (eGFR ≥50 and <80 mL/min/1.73 m2), moderate (eGFR ≥30 and <50 mL/min/1.73 m2), severe renal impairment (eGFR <30 mL/min/1.73 m2) and subjects with ESRD requiring haemodialysis following a single 400 mg dose of sofosbuvir. Relative to subjects with normal renal function (eGFR >80 mL/min/1.73 m2), the sofosbuvir AUC0-inf was 61%, 107% and 171% higher in mild, moderate and severe renal impairment, while the GS-331007 AUC0-inf was 55%, 88% and 451% higher, respectively. In subjects with ESRD, relative to subjects with normal renal function, sofosbuvir AUC0-inf was 28% higher when sofosbuvir was dosed 1 hour before haemodialysis compared with 60% higher when sofosbuvir was dosed 1 hour after haemodialysis. The AUC0-inf of GS-331007 in subjects with ESRD could not be reliably determined. However, data indicate at least 10-fold and 20-fold higher exposure to GS-331007 in ESRD compared to normal subjects when Sovaldi was administered 1 hour before or 1 hour after haemodialysis, respectively.

Haemodialysis can efficiently remove (53% extraction ratio) the predominant circulating metabolite GS-331007. A 4-hour haemodialysis session removed approximately 18% of administered dose. No dose adjustment is required for patients with mild or moderate renal impairment. The safety of Sovaldi has not been assessed in patients with severe renal impairment or ESRD (see section 4.4).

Hepatic impairment

The pharmacokinetics of sofosbuvir were studied following 7-day dosing of 400 mg sofosbuvir in HCV infected subjects with moderate and severe hepatic impairment (CPT class B and C). Relative to subjects with normal hepatic function, the sofosbuvir AUC0-24 was 126% and 143% higher in moderate and severe hepatic impairment, while the GS-331007 AUC0-24 was 18% and 9% higher, respectively. Population pharmacokinetics analysis in HCV infected subjects indicated that cirrhosis had no clinically relevant effect on the exposure to sofosbuvir and GS-331007. No dose adjustment of sofosbuvir is recommended for patients with mild, moderate and severe hepatic impairment (see section 4.2).

Paediatric population

The pharmacokinetics of sofosbuvir and GS-331007 in paediatric subjects have not been established (see section 4.2).

Pharmacokinetic/pharmacodynamic relationship(s)

Efficacy, in terms of rapid virologic response, has been shown to correlate with exposure to sofosbuvir as well as GS-331007. However, neither of these entities has been evidenced to be a general surrogate marker for efficacy (SVR12) at the therapeutic 400 mg dose.
5.3 Preclinical safety data
 In repeat dose toxicology studies in rat and dog, high doses of the 1:1 diastereomeric mixture caused adverse liver (dog) and heart (rat) effects and gastrointestinal reactions (dog). Exposure to sofosbuvir in rodent studies could not be detected likely due to high esterase activity; however, exposure to the major metabolite GS-331007 at the adverse dose was 29 times (rat) and 123 times (dog) higher than the clinical exposure at 400 mg sofosbuvir. No liver or heart findings were observed in chronic tox