Aims To evaluate the pharmacokinetic interaction between ritonavir and mefl
oquine.
Methods Healthy volunteers participated in two separate, nonfasted, three-t
reatment, three-period, longitudinal phramacokinetic studies. Study 1 (12 c
ompleted): ritonavir 200 mg twice daily for 7 days, 7 day washout, mefloqui
ne 250 mg once daily for 3 days then once weekly for 3 weeks, ritonavir res
tarted 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 admin
istered 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 c
oncentration (C-max) of mefloquine, its two enantiomers, and carboxylic aci
d 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 rito
navir 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 e
ffect on the ERMBT whereas ritonavir decreased activity by 98%.
Conclusions Ritonavir minimally affected mefloquine pharmacokinetics despit
e strong inhibition of CYP3A4 activity from a single 200 mg dose. Mefloquin
e had variable effects on ritonavir pharmacokinetics that were not explaine
d by hepatic CYP3A4 activity or ritonavir protein binding.