Pharmacokinetics of a Three-Way Drug Interaction Between Danoprevir, Ritonavir and the Organic Anion Transporting Polypeptide (OATP) Inhibitor Ciclosporin

Background Danoprevir (RG7227) is a potent macrocyclic inhibitor of the hepatitis C virus NS3/4A protease, which is currently in development in combination with low-dose ritonavir for the treatment of chronic hepatitis C infection. Danoprevir is a substrate of cytochrome P450 3A4, and the organic anion transporting polypeptides (OATP) 1B1 and 1B3. Objective The objective of this study was to evaluate the effect of a potent OATP inhibitor, ciclosporin, on danoprevir pharmacokinetics, when administered as danoprevir/ritonavir. The effect of danoprevir/ritonavir on ciclosporin pharmacokinetics was also investigated. Methods This was a single-dose, randomized, open-label, two-sequence, three-period, crossover study in healthy volunteers. In the first period, subjects were randomized to receive either a single oral dose of danoprevir 100 mg in combination with ritonavir 100 mg or a single oral dose of ciclosporin 100 mg. After a 14-day washout, patients were crossed over to receive the opposite treatment. In period 3, all subjects received the combination of danoprevir/ritonavir and ciclosporin following a 14-day washout from period 2. Blood samples were collected serially with each dose for pharmacokinetic assessment. Pharmacokinetic parameters were estimated using non-compartmental analysis. Geometric mean ratios (GMRs) and 90 % confidence intervals (CIs) were used to compare pharmacokinetic parameters [maximum concentration ( C max ), area under the concentration–time curve from time zero to infinity (AUC ∞ ), and concentration 12 h post-dose ( C 12h )] of danoprevir/ritonavir and ciclosporin when administered alone or in combination. Measures of safety and tolerability were also evaluated. Results A total of 18 subjects were enrolled, and 17 completed the study. The C max , AUC ∞ , and C 12h GMRs (90 % CI) when danoprevir/ritonavir and ciclosporin were co-administered versus danoprevir/ritonavir or ciclosporin alone were 7.22 (5.42–9.62), 13.6 (11.2–16.6), and 22.5 (17.4–29.3), respectively, for danoprevir, 1.97 (1.72–2.27), 2.23 (2.07–2.42), and 2.50 (2.22–2.81), respectively, for ritonavir, and 1.42 (1.29–1.57), 3.65 (3.27–4.08), and 6.15 (5.32–7.11), respectively, for ciclosporin. All treatments were well tolerated, with no laboratory abnormalities, and no clinically significant changes in vital signs, electrocardiograms, or physical examinations observed. Conclusions A significant drug–drug interaction was observed between ciclosporin and danoprevir/rit