Pharmacokinetic interaction between mefloquine and ritonavir in healthy volunteers.
OBJECTIVE
To evaluate the pharmacokinetic interaction between ritonavir and mefloquine.


METHODS
Healthy volunteers participated in two separate, nonfasted, three-treatment, three-period, longitudinal pharmacokinetic studies. Study 1 (12 completed): ritonavir 200 mg twice daily for 7 days, 7 day washout, mefloquine 250 mg once daily for 3 days then once weekly for 4 weeks, ritonavir restarted for 7 days simultaneously with the last mefloquine dose. Study 2 (11 completed): ritonavir 200 mg single dose, mefloquine 250 mg once daily for 3 days then once weekly for 2 weeks, ritonavir single dose repeated 2 days after the last mefloquine dose. Erythromycin breath test (ERMBT) was administered with and without drug treatments in study 2.


RESULTS
Study 1: Ritonavir caused less than 7% changes with high precision (90% CIs: -12% to 11%) in overall plasma exposure (AUC(0,168 h)) and peak concentration (Cmax) of mefloquine, its two enantiomers, and carboxylic acid metabolite, and in the metabolite/mefloquine and enantiomeric AUC ratios. Mefloquine significantly decreased steady-state ritonavir plasma AUC(0,12 h) by 31%, Cmax by 36%, and predose levels by 43%, and did not affect ritonavir binding to plasma proteins. Study 2: Mefloquine did not alter single-dose ritonavir pharmacokinetics. Less than 8% changes in AUC and Cmax were observed with high variability (90%CIs: -26% to 45%). Mefloquine had no effect on the ERMBT whereas ritonavir decreased activity by 98%.


CONCLUSIONS
Ritonavir minimally affected mefloquine pharmacokinetics despite strong inhibition of CYP3A4 activity from a single 200 mg dose. Mefloquine had variable effects on ritonavir pharmacokinetics that were not explained by hepatic CYP3A4 activity or ritonavir protein binding.
Khaliq
Y
Y
Clinical Investigation Unit, Department of Pharmacy, The Ottawa Hospital--General Campus, Ottawa, Ontario, Canada.
Gallicano
K
K
Tisdale
C
C
Carignan
G
G
Cooper
C
C
McCarthy
A
A
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001944:Breath Tests; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology*; D005260:Female; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D015767:Mefloquine / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D008954:Models, Biological; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013997:Time Factors
D000962:Antimalarials; D017320:HIV Protease Inhibitors; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D019438:Ritonavir; D015767:Mefloquine