Quantifying the pharmacology of antimalarial drug combination therapy.
Most current antimalarial drugs are combinations of an artemisinin plus a 'partner' drug from another class, and are known as artemisinin-based combination therapies (ACTs). They are the frontline drugs in treating human malaria infections. They also have a public-health role as an essential component of recent, comprehensive scale-ups of malaria interventions and containment efforts conceived as part of longer term malaria elimination efforts. Recent reports that resistance has arisen to artemisinins has caused considerable concern. We investigate the likely impact of artemisinin resistance by quantifying the contribution artemisinins make to the overall therapeutic capacity of ACTs. We achieve this using a simple, easily understood, algebraic approach and by more sophisticated pharmacokinetic/pharmacodynamic analyses of drug action; the two approaches gave consistent results. Surprisingly, the artemisinin component typically makes a negligible contribution (≪0.0001%) to the therapeutic capacity of the most widely used ACTs and only starts to make a significant contribution to therapeutic outcome once resistance has started to evolve to the partner drugs. The main threat to antimalarial drug effectiveness and control comes from resistance evolving to the partner drugs. We therefore argue that public health policies be re-focussed to maximise the likely long-term effectiveness of the partner drugs.
Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom.
Ian M
IM
Hastings
Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom.
Eva Maria
EM
Hodel
Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom.
Katherine
K
Kay
D000962:Antimalarials / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D037621:Artemisinins / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004352:Drug Resistance, Microbial / Q000187:drug effects; D004359:Drug Therapy, Combination; D006801:Humans; D008954:Models, Biological
D000962:Antimalarials; D037621:Artemisinins; C031327:artemisinin