Effect of faldaprevir on raltegravir pharmacokinetics in healthy volunteers

Abstract

Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor and an inhibitor of UDP-glucuronosyltransferase-1A1 (UGT1A1), which is involved in raltegravir clearance. Raltegravir, an HIV integrase inhibitor, may be used in combination with HCV treatment in HCV/HIV co-infected patients. In this open-label, 2-period, fixed-sequence study, 24 healthy volunteers (12 males) received faldaprevir 240 mg and raltegravir 400 mg in 2 treatment schedules (A and B) separated by a washout phase of ≥7 days: (A) twice-daily raltegravir (Days 1-3), once-daily raltegravir (Day 4); (B) twice-daily raltegravir and twice-daily faldaprevir (loading dose, Day 1), twice-daily raltegravir and once-daily faldaprevir (Days 2-5), once-daily raltegravir and once-daily faldaprevir (Day 6). Pharmacokinetics and safety were assessed over 132 hours post-dosing. Compared with raltegravir alone, co-administration with faldaprevir led to 2.7-fold and 2.5-fold increases in raltegravir geometric mean AUC(τ,ss) and C(max,ss), respectively, and a similar increase in raltegravir glucuronide metabolite exposure. No serious adverse events (AEs) were reported and no subject discontinued due to AEs. Faldaprevir and raltegravir co-administration was well tolerated and resulted in a moderate increase in raltegravir exposure.

Effect of Steady‐State Faldaprevir on Pharmacokinetics of Atorvastatin or Rosuvastatin in Healthy Volunteers: A Prospective Open‐Label, Fixed‐Sequence Crossover Study

“…Accordingly, the effect of faldaprevir on exposure to raltegravir, a substrate of P-gp and UGT1A1, is far less pronounced in HCV-infected patients than in healthy volunteers. 47 In the FDV phase 3 program, some patients took low doses of statins (3%) and showed no signs of elevated statin toxicity (data on file). Given the short treatment duration for HCV infection (6-12 weeks) as a result of the recent progress in HCV treatment, 48,49 it may be acceptable to temporarily interrupt statin treatment.…”

“…For example, the exposure to simeprevir and faldaprevir (both substrates of CYP3A4, OATP1B1/1B3, and NTCP) was 2‐ to 4‐fold higher in HCV‐infected patients than in healthy subjects, possibly because of lower activity of the hepatic uptake transporters and drug‐metabolizing enzyme in HCV‐infected patients. Accordingly, the effect of faldaprevir on exposure to raltegravir, a substrate of P‐gp and UGT1A1, is far less pronounced in HCV‐infected patients than in healthy volunteers …”