IngentaConnect Pharmacokinetic interaction between mefloquine and ritonavir in h...

Authors: Khaliq, Yasmin; Gallicano, Keith; Tisdale, Christine¹; Carignan, Germain; Cooper, Curtis²; McCarthy, Anne²

Source: British Journal of Clinical Pharmacology, Volume 51, Number 6, June 2001 , pp. 591-600(10)

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.

Keywords: cytochrome P450 3A4; erythromycin breath test; mefloquine; pharmacokinetic interaction; ritonavir

Document Type: Research article

DOI: 10.1046/j.1365-2125.2001.01393.x

Affiliations: 1: Pharmacy and 2: Medicine, and

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Pharmacokinetic interaction between mefloquine and ritonavir in healthy volunteers