The role of population pharmacokinetic-pharmacodynamic modelling in antimalarial chemotherapy

Simpson, Julie Anne (2001). The role of population pharmacokinetic-pharmacodynamic modelling in antimalarial chemotherapy. PhD thesis The Open University.



Despite the high rates of mortality and morbidity associated with malaria very few new antimalarial drugs are being developed. Hence there is much to be gained by optimising currently available antimalarials. Using pharmacokinetic and pharmacodynamic data from field trials where mefloquine was administered either alone or in combination with artesunate important information regarding optimal dosing for the clinician has been obtained. The pharmacokinetics of mefloquine were influenced relatively little, or not at all, by factors such as age, sex, or measures of acute malaria severity. Splitting the 25 mglkg dose of mefloquine monotherapy was associated with a 50% increase in oral bioavailability, and bioavailability increased by 20% for the split dose on the combination treatment. Oral bioavailability was also observed to be associated with more rapid parasite clearance, a surrogate outcome measure for cure. A mechanistic mathematical model was developed that describes the change in total parasite burden with time in vivo, in the presence of mefloquine. Estimates for the pharmacokinetic and pharmacodynamic parameters were obtained from population modelling of pharmacokinetic and in vitro pharmacodynamic data, both derived from the same region. Model simulations confirmed that, early in the evolution of resistance, conventional assessments of the therapeutic response 28 days after treatment underestimate considerably the level of resistance. Longer follow-up is required. The model also indicates that initial deployment of a lower (l5-mglkg) dose of mefloquine provides a greater opportunity for the selection of resistant mutants and would be expected to lead more rapidly to resistance than de novo use of the higher (25-mglkg) dose. From the modelling of malaria therapy data it was observed that even in the absence of drugs the patient parasitaemia versus time profiles varied greatly between both patients and parasites. Parasite multiplication rate every 48 hours was estimated to be approximately 8 fold.

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