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Antimicrobial Agents and Chemotherapy, December 2000, p. 3414-3424, Vol. 44, No. 12
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Mefloquine Pharmacokinetic-Pharmacodynamic Models: Implications for Dosing and Resistance

Julie A. Simpson,1,2 Emmeline R. Watkins,3 Ric N. Price,2,4 Leon Aarons,5 Dennis E. Kyle,6,dagger and Nicholas J. White1,2,*

Faculty of Tropical Medicine, Mahidol University,1 and Department of Immunology and Medicine, U.S. Armed Forces Research Institute of Medical Sciences,6 Bangkok, and Shoklo Malaria Research Unit, Mae Sod 63110, Tak Province,4 Thailand, and Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington,2 and Wellcome Trust Centre for the Epidemiology of Infectious Diseases, University of Oxford, Oxford,3 and School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester,5 United Kingdom

Received 11 October 1999/Returned for modification 11 April 2000/Accepted 11 September 2000

Antimalarial resistance develops and spreads when spontaneously occurring mutant malaria parasites are selected by concentrations of antimalarial drug which are sufficient to eradicate the more sensitive parasites but not those with the resistance mutation(s). Mefloquine, a slowly eliminated quinoline-methanol compound, is the most widely used drug for the treatment of multidrug-resistant falciparum malaria. It has been used at doses ranging between 15 and 25 mg of base/kg of body weight. Resistance to mefloquine has developed rapidly on the borders of Thailand, where the drug has been deployed since 1984. Mathematical modeling with population pharmacokinetic and in vivo and in vitro pharmacodynamic data from this region confirms that, early in the evolution of resistance, conventional assessments of the therapeutic response <= 28 days after treatment underestimate considerably the level of resistance. Longer follow-up is required. The model indicates that initial deployment of a lower (15-mg/kg) dose of mefloquine provides a greater opportunity for the selection of resistant mutants and would be expected to lead more rapidly to resistance than de novo use of the higher (25-mg/kg) dose.

* Corresponding author. Mailing address: Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Rd., Bangkok 10400, Thailand. Phone: (66 2) 246 0832. Fax: (66 2) 246 7795. E-mail: fnnjw{at}diamond.mahidol.ac.th.

dagger Present address: Division of Experimental Therapeutics, Walter Reed Army Institute of Research Washington, DC 20307.

Antimicrobial Agents and Chemotherapy, December 2000, p. 3414-3424, Vol. 44, No. 12
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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