The pharmacokinetic interaction between ivacaftor and ritonavir in healthy volunteers

Aims: The aim of this study was to determine the pharmacokinetic interaction between ivacaftor and ritonavir. Methods: A liquid chromatography mass spectrometry (LC–MS) method was developed for the measurement of ivacaftor in plasma. An open-label, sequential, cross-over study was conducted with 12 healthy volunteers. Three pharmacokinetic profiles were assessed for each volunteer: ivacaftor 150 mg alone (study A), ivacaftor 150 mg plus ritonavir 50 mg daily (study B), and ivacaftor 150 mg plus ritonavir 50 mg daily after two weeks of ritonavir 50 mg daily (study C). Results: Addition of ritonavir 50 mg daily to ivacaftor 150 mg resulted in significant inhibition of the metabolism of ivacaftor. Area under the plasma concentration–time curve from time 0 to infinity (AUC_{0-inf obv}) increased significantly in both studies B and C compared to study A (GMR [95% CI] 19.71 [13.18–31.33] and 19.77 [14.0–27.93] respectively). Elimination half-life (t_1/2) was significantly longer in both studies B and C compared to study A (GMR [95% CI] 11.14 [8.72–13.62] and 9.72 [6.68–12.85] respectively). There was no significant difference in any of the pharmacokinetic parameters between study B and study C. Conclusion: Ritonavir resulted in significant inhibition of the metabolism of ivacaftor. These data suggest that ritonavir may be used to inhibit the metabolism of ivacaftor in patients with cystic fibrosis (CF). Such an approach may increase the effectiveness of ivacaftor in ‘poor responders’ by maintaining higher plasma concentrations. It also has the potential to significantly reduce the cost of ivacaftor therapy.