The overall aim of this NIAID International Research in Infectious Diseases R01 application from a new investigator in Malawi is to learn, using pharmacokinetic-pharmacodynamic (PK-PD) models, how best to combine antimalarial drugs to deter the emergence of resistance. The return of chloroquine antimalarial efficacy in Malawi presents a unique historic opportunity to develop and test rational strategies for combining antimalarial drugs in ways that will prolong their useful therapeutic lives. In the context of an NIAID-funded longitudinal clinical trial comparing the ability of different chloroquine combinations to block reemergence of chloroquine resistance, this grant will support PK-PD studies to determine the "window of selection" during which chloroquine should be protected by partner drugs to prevent selection of resistant parasites. Using population PK models blood drug concentrations of chloroquine and partner drugs will be measured and key PK parameters will be determined. The drug concentrations and times after treatment at which resistant parasites appear in children repeatedly treated with chloroquine alone and in combination with artesunate, azithromycin and atovaquone-progunail will be measured using both in vivo and in vitro approaches. The results of these studies will be used to identify PK-PD characteristics of drug combinations that best prevent the emergence and spread of chloroquine resistance, and will inform the choices of partner drugs for the next generation of combination therapies. This project will also help to establish a sustainable clinical pharmacology research capacity at the University of Malawi College of Medicine linked to NIAID-supported clinical trials and molecular epidemiology studies.