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Pharmacokinetic interaction between mefloquine and ritonavir in healthy volunteers
Author(s) -
Khaliq Yasmin,
Gallicano Keith,
Tisdale Christine,
Carignan Germain,
Cooper Curtis,
McCarthy Anne
Publication year - 2001
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.2001.01393.x
Subject(s) - ritonavir , mefloquine , pharmacokinetics , pharmacology , cmax , metabolite , drug interaction , medicine , viral load , chloroquine , immunology , malaria , human immunodeficiency virus (hiv) , antiretroviral therapy
Aims 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 ( C max ) 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%, C max 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 C max 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.