Incorporating Stage-Specific Drug Action into Pharmacological Modeling of Antimalarial Drug Treatment

Pharmacological modeling of antiparasitic treatment based on a drug's pharmacokinetic and pharmacodynamic properties plays an increasingly important role in identifying optimal drug dosing regimens and predicting their potential impact on control and elimination programs. Conventional modeling of treatment relies on methods that do not distinguish between parasites at different developmental stages. This is problematic for malaria parasites, as their sensitivity to drugs varies substantially during their 48-h developmental cycle. We investigated four drug types (short or long half-lives with or without stage-specific killing) to quantify the accuracy of the standard methodology. The treatment dynamics of three drug types were well characterized with standard modeling. The exception were short-half-life drugs with stage-specific killing (i.e., artemisinins) because, depending on time of treatment, parasites might be in highly drug-sensitive stages or in much less sensitive stages. We describe how to bring such drugs into pharmacological modeling by including additional variation into the drug's maximal killing rate. Finally, we show that artemisinin kill rates may have been substantially overestimated in previous modeling studies because (i) the parasite reduction ratio (PRR) (generally estimated to be 10(4)) is based on observed changes in circulating parasite numbers, which generally overestimate the "true" PRR, which should include both circulating and sequestered parasites, and (ii) the third dose of artemisinin at 48 h targets exactly those stages initially hit at time zero, so it is incorrect to extrapolate the PRR measured over 48 h to predict the impact of doses at 48 h and later.