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 (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.

Figure 1

Design of studies 1 and 2. Blood samples were collected over 12 h for ritonavir and over 168 h (7 days) for mefloquine. RTV: ritonavir 200 mg every 12 h; MFQ: mefloquine 250 mg; ERMBT: erythromycin breath test; PK: pharmacokinetics.

Figure 2

Mean (± s.d.) plasma concentrations of (a) multiple-dose ritonavir in 10 healthy subjects (study 1), and (b) single-dose ritonavir in 11 healthy individuals (study 2) in the absence (○) and presence (□) of mefloquine. Missing error bars are outside the lower range of the y-axis.

Figure 3

Mean plasma concentrations of (a) the (+) RS (triangles;) and (–) SR (diamonds) enantiomers of mefloquine, and (b) racemic mefloquine (circles) and the carboxylic acid metabolite of mefloquine (squares) in 12 healthy subjects in the absence (solid lines) and presence (dotted lines) of ritonavir.