Abstract
It has been suggested recently, based on pharmacokinetic-pharmacodynamic modelling exercises, that twice daily dosing of artemisinins increases malaria parasite killing and so could “dramatically enhance and restore drug effectiveness” in artemisinin resistant P. falciparum malaria infections. It was recommended that split dosing should be incorporated into all artemisinin combination regimen designs. To explain why parasite clearance rates were not faster with split dose regimens it was concluded that splenic malaria parasite clearance capacity was readily exceeded, resulting in the accumulation of dead parasites in the circulation, that parasite clearance was therefore an unreliable measure of drug efficacy, and instead that human immunity is the primary determinant of clearance rates. To test these various hypotheses we performed a logistic meta-regression analysis of cure rates from all falciparum malaria treatment trials (n = 40) with monotherapy arms containing artemisinin or a derivative (76 arms). There was no evidence that split dosing enhanced cure rates.
Highlights
When artemisinin and its derivatives were first evaluated in the treatment of malaria a variety of doses and dosing schedules were assessed
Correspondence and requests for materials should be addressed to N.J.W. www.nature.com/scientificreports/. Follows logically from this model construct that the effect of each dose is equivalent when suitably spaced out in time, i.e. if the first dose reduced the number of parasites by a factor of 104 a dose 6–8 hours later would reduce numbers by 104 fold resulting in a 108 total reduction
It was conjectured that this " saturation" of clearance capacity resulted in the accumulation of dead parasites in the circulation thereby dissociating parasite killing from parasite clearance
Summary
The radical suggestions of the Liverpool group are not supported by clinical observations. If immunity is the primary determinant of parasite clearance rates it cannot explain why parasite clearance rates are twice as slow in patients of similar age and geographic origin, who have K13 mutant artemisinin-resistant compared with K13 wild type artemisinin-sensitive parasites[19,24,25,26,27,28]. In studies where the effects of immunity, or age as a surrogate of cumulative exposure, on parasite clearance rates have been quantitated, the effects are much smaller than the effects of artemisinin resistance[19,24,29,30]. In assessing treatment responses in artemisinin resistant falciparum malaria the hypothesis that human immunity is the primary determinant of parasite clearance rate[17] does not fit the facts
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