Population pharmacokinetics of artesunate and amodiaquine in African children

Abstract

BackgroundPharmacokinetic (PK) data on amodiaquine (AQ) and artesunate (AS) are limited in children, an important risk group for malaria. The aim of this study was to evaluate the PK properties of a newly developed and registered fixed dose combination (FDC) of artesunate and amodiaquine.MethodsA prospective population pharmacokinetic study of AS and AQ was conducted in children aged six months to five years. Participants were randomized to receive the new artesunate and amodiaquine FDC or the same drugs given in separate tablets. Children were divided into two groups of 70 (35 in each treatment arm) to evaluate the pharmacokinetic properties of AS and AQ, respectively. Population pharmacokinetic models for dihydroartemisinin (DHA) and desethylamodiaquine (DeAq), the principal pharmacologically active metabolites of AS and AQ, respectively, and total artemisinin anti-malarial activity, defined as the sum of the molar equivalent plasma concentrations of DHA and artesunate, were constructed using the non-linear mixed effects approach. Relative bioavailability between products was compared by estimating the ratios (and 95% CI) between the areas under the plasma concentration-time curves (AUC).ResultsThe two regimens had similar PK properties in young children with acute malaria. The ratio of loose formulation to fixed co-formulation AUCs, was estimated as 1.043 (95% CI: 0.956 to 1.138) for DeAq. For DHA and total anti-malarial activity AUCs were estimated to be the same. Artesunate was rapidly absorbed, hydrolysed to DHA, and eliminated. Plasma concentrations were significantly higher following the first dose, when patients were acutely ill, than after subsequent doses when patients were usually afebrile and clinically improved. Amodiaquine was converted rapidly to DeAq, which was then eliminated with an estimated median (range) elimination half-life of 9 (7 to 12) days. Efficacy was similar in the two treatments groups, with cure rates of 0.946 (95% CI: 0.840–0.982) in the AS+AQ group and 0.892 (95% CI: 0.787 – 0.947) in the AS/AQ group. Four out of five patients with PCR confirmed recrudescences received AQ doses < 10 mg/kg. Both regimens were well tolerated. No child developed severe, post treatment neutropaenia (<1,000/μL). There was no evidence of AQ dose related hepatotoxicity, but one patient developed an asymptomatic rise in liver enzymes that was resolving by Day-28.ConclusionThe bioavailability of the co-formulated AS-AQ FDC was similar to that of the separate tablets for desethylamodiaquine, DHA and the total anti-malarial activity. These data support the use this new AS-AQ FDC in children with acute uncomplicated falciparum malaria.

Population Pharmacokinetic and Pharmacodynamic Modeling of Amodiaquine and Desethylamodiaquine in Women with Plasmodium vivax Malaria during and after Pregnancy

“…The pharmacokinetic properties of amodiaquine and desethylamodiaquine in adults and children have been described mainly using a noncompartmental approach (20,38,40,53,(63)(64)(65). Three previous studies have described the pharmacokinetic properties of amodiaquine and desethylamodiaquine in nonpregnant adults and children using nonlinear mixed-effects modeling (2,17,23).…”

“…The pharmacokinetic properties of amodiaquine and desethylamodiaquine have been investigated in healthy volunteers, patients with P. falciparum malaria, and children (2,17,20,23,37,38,40,45,52,53,60,64,65). A multiphasic exponential decline has been suggested for both amodiaquine and desethylamodiaquine, with terminal elimination half-lives of approximately 10 h and 10 days, respectively (25).…”

Timing is everything for artemisinin action

“…A practical implication is that artemisinins dosed more frequently or with a longer halflife will improve time above inhibition concentration (16) as long as the toxic effects of bone marrow suppression do not appear (19). Another implication is that the mechanism of action or activation of drug may be different at different times in the erythrocyte life cycle, which would explain the timedependent pulse drug IC 50 .…”

Pharmacokinetics of Amodiaquine and Desethylamodiaquine in Pregnant and Postpartum Women with Plasmodium vivax Malaria

“…According to the World Health Organization, there is no evidence to contraindicate the use of amodiaquine during pregnancy, although data are limited and additional safety data are needed (2, 23, 25). The pharmacokinetic properties of AQ and DEAQ have been described for children and adults (5,7,13,16,19,21,29) but not for pregnancy. The pharmacokinetic properties of many antimalarials are altered during pregnancy (27).…”