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Pharmacokinetic interaction between mefloquine and ritonavir in healthy volunteers

  1. Yasmin Khaliq1,2,
  2. Keith Gallicano1,3,4,
  3. Christine Tisdale2,
  4. Germain Carignan1,4,
  5. Curtis Cooper3,
  6. Anne McCarthy3

Article first published online: 24 JAN 2002

DOI: 10.1046/j.1365-2125.2001.01393.x

Issue

British Journal of Clinical Pharmacology

British Journal of Clinical Pharmacology

Volume 51, Issue 6, pages 591–600, June 2001

Additional Information

How to Cite

Khaliq, Y., Gallicano, K., Tisdale, C., Carignan, G., Cooper, C. and McCarthy, A. (2001), Pharmacokinetic interaction between mefloquine and ritonavir in healthy volunteers. British Journal of Clinical Pharmacology, 51: 591–600. doi: 10.1046/j.1365-2125.2001.01393.x

Author Information

  1. 1

    Clinical Investigation Unit, Departments of

  2. 2

    Pharmacy and

  3. 3

    Medicine, and

  4. 4

    Ottawa Hospital Research Institute, The Ottawa Hospital – General Campus, Ottawa, Ontario, Canada

* Keith Gallicano, PhD, Axelson Biopharma Research, Inc., Suite 309, 2083 Alma Street, Vancouver, B.C., Canada V6R 4N6. Tel.: (604) 222–4184; Fax: (604) 222 3141; E-mail: kgallicano@axelson.net

Publication History

  1. Issue published online: 24 JAN 2002
  2. Article first published online: 24 JAN 2002
  3. Received 28 September 2000,accepted 16 February 2001.

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Keywords:

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

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.

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