Pharmacokinetic interaction between mefloquine and ritonavir in healthy volunteers

Aims To evaluate the pharmacokinetic interaction between ritonavir and mefloquine. Methods Healthy volunteers participated in two separate, nonfasted, three-treatment, three-period, longitudinal phramacokinetic 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 3 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 3 weeks, ritonavir single dose repeated 3 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-doss 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.