Pharmacokinetic interactions between ritonavir and quinine in healthy volunteers following concurrent administration.
OBJECTIVE
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.
Soyinka
Julius O
JO
Department of Pharmaceutical Chemistry, Obafemi Awolowo University, Ile-Ife, Nigeria.
Onyeji
Cyprian O
CO
Omoruyi
Sharon I
SI
Owolabi
Adegbenga R
AR
Sarma
Pullela V
PV
Cook
James M
JM
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000627:therapeutic use; D000962:Antimalarials / Q000627:therapeutic use; D018592:Cross-Over Studies; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D011802:Quinidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D011803:Quinine / Q000627:therapeutic use*; D019438:Ritonavir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D019380:Anti-HIV Agents; D000962:Antimalarials; D017320:HIV Protease Inhibitors; C013569:3-hydroxyquinidine; D011803:Quinine; D011802:Quinidine; D019438:Ritonavir