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Artemisinin derivatives are key to the current global treatment approach for malaria. However, much remains unknown regarding the pharmacokinetics of these agents, particularly in children and pregnant women, two groups highly vulnerable to development of severe malaria infection. In this thesis, nonlinear mixed effects modeling is used to characterize the pharmacokinetics of the artemisinin derivative artesunate and its active metabolite, dihydoartemisinin (DHA), in children and in pregnant women.
Chapter 1 of this thesis contains a general review of the clinical pharmacokinetic findings for artesunate and DHA following artesunate administration by the intravenous, intramuscular, oral and rectal routes. Chapter 2 presents a population pharmacokinetic model utilizing both pediatric and adult data from one Phase II and four Phase III clinical trials evaluating the combination agent pyronaridine tetraphosphate/artesunate. The focus of the modeling described in this chapter is the evaluation of the effects of body size and gender on the pharmacokinetics of artesunate and DHA in pediatric patients with uncomplicated malaria. Chapter 3 consists of a population pharmacokinetic model built utilizing plasma artesunate and DHA concentrations from 26 parasitemic second and third trimester pregnant women and 25 parasitemic non-pregnant female controls in the Democratic Republic of Congo who received 200 mg oral artesunate.
The model described in Chapter 2 is a simultaneously implemented parent-metabolite model consisting of a one compartment model for artesunate, a one compartment model for DHA, and first-order artesunate absorption. Various approaches for incorporating body size on artesunate and DHA apparent clearance and volume of distribution parameters were evaluated, with a linear body surface area model and an allometric scaling model both proving satisfactory. The effect of gender was modeled on artesunate and DHA apparent clearance and volume terms. Only the effect of gender on DHA apparent clearance could be estimated with reasonable precision, with the 95% confidence interval for the effect being almost wholly contained within the predefined 0.75 to 1.25 no relevant clinical effect interval. The model described in Chapter 3 consists of a one compartment model for artesunate, a one compartment model for DHA, and mixed zero-order, lagged first order absorption of artesunate. In this model, pregnancy was found to have a marked effect on DHA apparent clearance, with a pregnancy-associated increase in DHA apparent clearance of 42.3%.
The models described in this thesis indicate that, for a given mg/kg dose of artesunate, both young children and pregnant women would be expected, on average, to display lower DHA concentrations than would be observed following administration of the same mg/kg dose to non-pregnant adults. Suboptimal dosing has clinical implications for the individual as well as potential implications regarding parasite susceptibility. Given this, the findings of the research described in this thesis highlight the necessity of investigations designed to comprehensively characterize the pharmacokinetics of artesunate and DHA in these two highly susceptible populations.