Modeling the Evolution of Antimalarial Drug Resistance for Clinically Realistic Pharmacokinetics

Prevalent in sub-Saharan Africa and Asia, malaria, caused by the parasite Plasmodium affects over 200 million people yearly. One widely used antimalarial is the antifolate pyrimethamine. However, previous research has shown that specific point mutations in the parasite’s genome leads to higher pyrimethamine resistance, and a genetically fitter allele. Using pharmacokinetic theory, we model a clinically realistic dynamic environment of pyrimethamine. Population genetics gives us a framework to analyze the evolutionary implications of this dynamic environment. We discover that the fitness peak alleles change under this clinically realistic dynamic environment than previously observed in past literature. Thus, we observe that other measures of fitness like IC50 obscure evolutionary nuances in the case of pyrimethamine. Finally, we model the evolutionary implications of changing drug dosage schedule and patient non-compliance.