Artemisinin-based combination therapy (ACT) is the current first-line treatment of malaria . At present, the forms of ACT recommended by the World Health Organization (WHO) contain artemether (AM) plus lumefantrine (LF), artesunate (AS) plus either amodiaquine (AQ), mefloquine (MQ), pyronaridine (PN) or sulphadoxine-pyrimethamine (SP), and dihydroartemisinin (DHA) plus piperaquine (PPQ) . While hundreds of thousand courses of ACT are deployed each year , there is a limited number of studies measuring levels of drug exposure and relating it to treatment efficacy and safety.
Acquiring this information is paramount in order to optimize treatment and, especially, prevent resistance which may result from inadequate dosing. One of the main questions is to know if giving the recommended dose produces the same level of exposure in all, or otherwise what proportion or categories of subjects, and under which circumstances, would be systematically over- or under-dosed.
In other words, one needs to know if dosing regimens are adequate or if there are systematic dosing errors in which populations, especially on account of inter-subject variability and special groups like children and pregnant women. There is evidence that SP was systematically under-dosed in children and that the lower drug levels have contributed to the emergence of parasite resistance to this drug [3, 4]. The situation is further complicated by the fact that the target doses and therapeutic windows have been established based mostly on data in adults, and assume all patients require the same level of exposure, while, for instance, the contribution of immunity to parasite clearance will change with age and malaria transmission.
In this respect, one will need to know how the pharmacokinetics contributes to efficacy or safety outcomes. Examples of proposed surrogate efficacy correlates are day 7 drug plasma concentrations for LF [5–7] and the time for drug plasma concentrations to fall below 500 μg/l (the minimal inhibitory concentration, MIC) for MQ .
Treating with a wrong dose may have both individual and general consequences. Over-exposure increases the risk of toxicity; under-dosing may lead to treatment failure, but also carries the risk of selecting for drug-resistant parasites, which can spread to the rest of the population [9–12].
Two clinical trials found that AM-LF was highly efficacious in Tanzania, but much less effective (71% cure rate) in Cambodia [13, 14]. The cure rate in Cambodia increased to 86.5% in the subsequent years when 250 ml milk and coconut biscuits were provided with each dose of the study medication to increase drug absorption . These findings raised the question of the factors that could have contributed to the lower efficacy of AM-LF in the Cambodian population. Parasite susceptibility is indeed a potential explanation [15–24], although no known molecular marker exists at the moment. Another possibility is that differences in drug levels induced by genetic or other factors could explain the difference in drug response between these two populations.
The objectives of this paper were to characterize the population pharmacokinetics of AS, DHA, MQ and PPQ in Cambodian patients and AM and LF in Tanzanian patients and to identify demographic and other factors that could explain variability in drug levels. In addition, day 7 concentrations have been shown to be a good surrogate marker of treatment success and model based-simulations of LF were performed to predict the proportion of patients with concentrations below the proposed day 7 cut-off values.