Pharmacokinetic determinants of the window of selection for antimalarial drug resistance

The selection and spread of antimalarial drug resistance pose enormous challenges to the health of people living in tropical countries. Most antimalarial drugs are slowly eliminated and so, following treatment in areas of endemicity, 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 of the window only when blood concentrations have fallen below the MIC, the window of selection for de novo resistance is narrower than that for resistance acquired elsewhere. The windows were examined for the currently available antimalarials. Drugs with elimination half-lives of less than 1 day, such as the artemisinins and quinine, do not select for resistance during the elimination phase.