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

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Malaria is widespread across some areas of the world, most of which also bear the brunt of the human immunodeficiency virus (HIV) pandemic, resulting in a high incidence of co‐infection of both diseases.

• Ritonavir, a HIV protease inhibitor, and quinine, an antimalarial agent effective against multidrug‐resistant Plasmodium falciparum, are likely to be administered concurrently for treatment of patients with HIV and malaria.

• Both drugs are metabolized to a significant extent by CYP3A4 and ritonavir is a potent inhibitor of this enzyme.

WHAT THIS STUDY ADDS

• With increasing access to antiretroviral drugs, it is important that potential interactions between therapies for HIV and malaria infections are investigated.

• In this study, concurrent administration of ritonavir with quinine was found to be associated with marked elevation in the plasma levels of the antimalarial and a pronounced decrease in plasma concentrations of 3‐hydroxyquinine, the major metabolite of quinine.

• There was also a modest but significant increase (P < 0.05) in plasma concentrations of ritonavir in the presence of quinine.

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_½ of ritonavir.

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

DOI: 10.1111/j.1365-2125.2009.03566.x

View this article

• Full article (html)
• Enhanced article (html)
• PDF
• References