Pharmacokinetic determinants of the window of selection for antimalarial drug resistance

Abstract

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.

FIG. 1.

Window of selection for resistant malaria parasites acquired from elsewhere (A) and de novo resistance in newly acquired infections exposed to residual antimalarial drug concentrations (B). Blood concentrations of an antimalarial drug (t_1/2, 1 week) are shown by the thick line. (B) The window opens when the usually single parasite resistant de novo, which emerges from the liver, and its progeny (R¹) can survive and grow; i.e., the blood concentrations have fallen to or below the MIC for this level of resistance. The majority population of the sensitive sister parasites (S¹) is eliminated. The window closes when the growth of sensitive parasites (S²) emerging from the liver outstrips the growth of the resistant parasites (R²), such that by the time that the S² parasite population reaches 10⁸, there are <10⁷ R² parasites.

FIG. 2.

Relationship between the selection window (vertical lines) for scenario A (de novo resistance) and the drug t_1/2 in the case of p (EC₅₀ for resistance/EC₅₀ for susceptibility) equal to 2 (A), p equal to 4 (B), and p equal to 6 (C). The arrows point to the t_1/2 value below which no window of selection occurs. n, slope of concentration-effect relationship; a, ratio of maximum blood or plasma concentration to EC₅₀.

FIG. 3.

Window opening times for scenario B for p equal to 1.5 (full circles), p equal to 2 (empty circles), and p equal to 2.5 (empty triangles). Note that the scale is different in each graph.

FIG. 4.

Windows of selection for scenario A (vertical lines) and scenario B (solid lines) for different t_1/2s in the case of p equal to 2, n equal to 5, and a equal to 5.

FIG. 5.

Relationship between the duration of windows of selection for scenario A and scenario B for p equal to 2. Each line is for a given value of n for all levels of a.