In 2013 there were an estimated 198 million clinical cases of malaria and 584,000 deaths from malaria worldwide. Nearly all deaths and most serious morbidity are due to the parasite Plasmodium falciparum. The World Health Organization currently recommends an artemisinin derivative combined with another antimalarial drug as the first line treatment of falciparum malaria. At the individual level these antimalarials improve treatment outcomes, and at the population level reduce malaria transmission and minimize the selection of drug resistant parasites. Alarmingly, resistance has developed in South East Asia over the last few years to the artemisinin derivatives, the last remaining highly effective antimalarial drugs. Fortunately, resistance currently only manifests as a delay to clearance in treated patients – inferred to be due to a reduced rate of killing of young parasites in the blood, rather than complete treatment failure. However, over time the WHO expects the level of resistance to increase, leading to complete treatment failure from an individual’s perspective and loss of a major public health control strategy from a population perspective.
In collaboration with A/Prof Julie Simpson and Dr Sophie Zaloumis (Centre for Epidemiology and Biostatistics) and Prof Leanne Tilley and team (Bio21), in this project we are developing new pharmacokinetic-pharmacodynamic models of antimalarial treatment strategies in order to delay or reverse this resistance and, through our links with WHO, contribute to efforts to prolong the life of the artemisinin derivatives.
In research to date, we have identified in vitro markers of resistance and used PK-PD models to suggest that a fourth treatment dose may improve treatment outcomes (Dogovski et al, PBIOL 2015). Furthermore, in that work and our recent review (Simpson et al, AAPSJ 2014), we have argued that current models for the artemisinin derivatives do not take into account two critical factors that determine treatment outcome: (1) the specific action of the drug on sensitive and resistant strains; and (2) the influence of patient immunity. These major issues are the topic of current research under the CRE.