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 C(max) and AUC(T)[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 C(max) (1.80 +/- 0.12 vs. 0.96 +/- 0.09 mg l(-1)) and AUC(0-48h) (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 C(max), AUC and elimination T((1/2)) of ritonavir.

Conclusions: Downward dosage adjustment of quinine appears necessary when concurrently administered with ritonavir.

Figure 1

Scheme depicting the study design

Figure 2

Mean (±) SD plasma concentration vs. time profiles of quinine (a) and 3-hydroxyquinine (b) following administrations of a single 600-mg oral dose of quinine sulphate with or without concurrent multiple oral doses of ritonavir (200 mg 12 hourly for 9 days) to each of 10 healthy volunteers. The quinine dose was co-administered with the 15th dose (day 8) of ritonavir. (A) Quinine alone (); Quinine with Ritonavir (); (B) 3-hydroxyquinine alone (); 3-hydroxyquinine in presence of ritonavir ()

Figure 3

Mean (±) SD plasma concentration vs. time profiles of ritonavir following administration of multiple doses of the drug alone (200 mg 12 hourly for 9 days) or with concurrent single oral doses of quinine (600 mg) to each of 10 healthy volunteers. Quinine was co-administered with the 15th dose (day 8) of ritonavir. Ritonavir alone (); Ritonavir in presence of quinine ()