In silico investigation of the decline in clinical efficacy of artemisinin combination therapies due to increasing artemisinin and partner drug resistance [Mechanisms of Resistance]

Antimalarial treatment currently relies on an artemisinin derivative and a longer acting partner drug. With the emergence of resistance to the artemisinin derivatives and the potential pressure this exerts on the partner drugs, the impact of resistance to each drug on efficacy needs to be investigated. An in silico exploration of dihydroartemisinin-piperaquine and mefloquine-artesunate, two commonly used artemisinin-based combination therapies in Southeast Asia, was performed. The percentage of treatment failures was simulated from a within-host pharmacokinetic-pharmacodynamic (PKPD) model assuming parasites developed increasing levels of (i) artemisinin derivative resistance or (ii) concomitant resistance to both the artemisinin derivative and partner drug. Because the exact nature of how resistant Plasmodium falciparum parasites respond to treatment is unknown, we examined the impact on treatment failure rates of artemisinin resistance that either: (i) reduced the maximal killing rate (k_max); (ii) increased the concentration of drug required for 50% killing (EC50); or (iii) shortened the window of parasite stages that are susceptible to artemisinin derivatives until it has no effect on the ring stages. The loss of the ring stage activity of the artemisinin derivative caused the greatest increase in the treatment failure rate, and this result held irrespective of whether partner drug resistance was assumed present or not. To capture the uncertainty around how artemisinin derivative and partner drug resistance impact the assumed concentration-killing effect relationship, a variety of changes to this relationship should be considered when using within-host PKPD models to simulate clinical outcomes to guide treatment strategies for resistant infections.

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