Pharmacokinetic interaction between mefloquine and ritonavir in healthy volunteers

Abstract

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.