Pharmacokinetic interactions between ritonavir and quinine in healthy volunteers following concurrent administration

Abstract

Aims: To evaluate the pharmacokinetic interactions between ritonavir and quinine in healthy volunteers. Methods: Ten healthy volunteers were each given 600-mg single oral doses of quinine alone, ritonavir alone (200 mg every 12 h for 9 days), and quinine in combination with ritonavir, in a three-period pharmacokinetic nonrandomized sequential design study. Quinine was co-administered with the 15th dose of ritonavir. Blood samples collected at predetermined time intervals were analysed for ritonavir, quinine and its major metabolite, 3-hydroxyquinine, using a validated high-performance liquid chromatography method. Results: Concurrent ritonavir administration resulted in about fourfold increases in both the Cmax and AUCT C max 2.79 ± 0.22 vs. 10.72 ± 0.32 mg l-1, 95% confidence interval (CI) 7.81, 8.04; AUC 50.06 ± 2.52 vs. 220.47 ± 6.68 mg h-1 l-1, 95% CI 166.3, 175.3, a significant increase (P < 0.01) in the elimination half-life (11.15 ± 0.80 vs. 13.37 ± 0.33 h, 95% CI 1.64, 2.77) and about a 4.5-fold decrease in CL/F (12.01 ± 0.61 vs. 2.71 ± 0.09 l h-1) of quinine. Also, with ritonavir, there was a pronounced reduction of AUC(metabolite)/AUC(unchanged drug) ratio of quinine (1.35 ± 0.10 vs. 0.13 ± 0.02) along with a marked decrease in Cmax (1.80 ± 0.12 vs. 0.96 ± 0.09 mg l-1) and AUC0-48h (62.80 ± 6.30 vs. 25.61 ± 2.44 mg h-1 l-1) of the metabolite. Similarly, quinine caused modest but significant increases (P < 0.01) in the Cmax, AUC and elimination T1/2 of ritonavir. Conclusions: Downward dosage adjustment of quinine appears necessary when concurrently administered with ritonavir. © 2010 The British Pharmacological Society.