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Antimicrob. Agents Chemother. doi:10.1128/AAC.00903-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The pharmacokinetic determinants of the window of selection for antimalarial drug resistance

Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Vaccinology, Churchill Hospital, Oxford OX3 7LJ, UK

^* To whom correspondence should be addressed. Email: nickw{at}tropmedres.ac.

	Abstract

The selection and spread of antimalarial drug resistance poses an enormous challenge to the health of people living in tropical countries. Most antimalarial drugs are slowly eliminated and so, following treatment in endemic areas, provide a gradient of concentrations to which newly acquired parasites are exposed. There is a variable period during which a new blood stage infection with resistant malaria parasites can emerge from the liver and subsequently produce gametocyte densities sufficient for transmission, while reinfection by sensitive parasites is still suppressed. This "window of selection" drives the spread of resistance. We have examined the factors which determine the duration of this window, and thus the resistance selection pressure. The duration ranges from zero to several months and is dependent on the degree of parasite resistance, the slope of the concentration-effect relationship, and the elimination kinetics of the antimalarial drug. The time at which the window opens and the duration of opening are both linear functions of the terminal elimination half-life. Because of competition from sibling susceptible parasites, the greater risks of extinction with low starting numbers, and opening only when blood concentrations have fallen below the minimum inhibitory concentration, the window of selection for de-novo resistance is narrower than for resistance acquired from elsewhere. The window was examined for currently available antimalarials. Drugs such as the artemisinins and quinine with elimination half-lives of less than one day do not select during the elimination phase.