• Adherence and population pharmacokinetic properties of amodiaquine when used for seasonal malaria chemoprevention in African children

      Ding, J; Coldiron, ME; Assao, B; Guindo, O; Blessborn, D; Winterberg, M; Grais, RF; Koscalova, A; Langendorf, C; Tarning, J (American Society for Clinical Pharmacology and Therapeutics, 2019-10-25)
      Poor adherence to seasonal malaria chemoprevention (SMC) might affect the protective effectiveness of SMC. Here, we evaluated the population pharmacokinetic properties of amodiaquine and its active metabolite, desethylamodiaquine, in children receiving SMC under directly‐observed ideal conditions (n=136), and the adherence of SMC at an implementation phase in children participating in a case‐control study to evaluate SMC effectiveness (n=869). Amodiaquine and desethylamodiaquine concentration‐time profiles were described simultaneously by two‐compartment and three‐compartment disposition models, respectively. The developed methodology to evaluate adherence showed a sensitivity of 65‐71% when the first dose of SMC was directly observed and 71‐73% when no doses were observed in a routine programmatic setting. Adherence simulations and measured desethylamodiaquine concentrations in the case‐control children showed complete adherence (all doses taken) in less than 20% of children. This result suggests that more efforts are needed urgently to improve the adherence to SMC among children in this area.
    • Severe acute malnutrition results in lower lumefantrine exposure in children treated with artemether-lumefantrine for uncomplicated malaria

      Chotsiri, P; Denoeud-Ndam, L; Baudin, E; Guindo, O; Diawara, H; Attaher, O; Smit, M; Guerin, PJ; Duombo, OK; Weisner, L; et al. (American Society for Clinical Pharmacology and Therapeutics, 2019-06-01)
      Severe acute malnutrition (SAM) has been reported to be associated with increased malaria morbidity in Sub‐Saharan African children and may affect the pharmacology of antimalarial drugs. This population pharmacokinetic‐pharmacodynamic study included 131 SAM and 266 non‐SAM children administered artemether‐lumefantrine twice daily for 3 days. Lumefantrine capillary plasma concentrations were adequately described by two transit‐absorption compartments followed by two distribution compartments. Allometrically scaled body weight and an enzymatic maturation effect were included in the pharmacokinetic model. Mid‐upper arm circumference (MUAC) was associated with decreased absorption of lumefantrine (25.4% decrease per 1 cm reduction). Risk of recurrent malaria episodes (i.e. reinfection) were characterised by an interval‐censored time‐to‐event model with a sigmoid EMAX‐model describing the effect of lumefantrine. SAM children were at risk of under‐exposure to lumefantrine and an increased risk of malaria reinfection compared to well‐nourished children. Research on optimised regimens should be considered for malaria treatment in malnourished children.