Population pharmacokinetics of amodiaquine and desethylamodiaquine in pediatric patients with uncomplicated falciparum malaria.
The study aimed to characterize the population pharmacokinetics of amodiaquine (AQ) and its major metabolite N-desethylamodiaquine (N-DEAQ), and to assess the correlation between exposure to N-DEAQ and treatment outcome. Blood samples from children in two studies in Zanzibar and one in Papua New Guinea were included in the pharmacokinetic analysis (n = 86). The children had been treated with AQ in combination with artesunate or sulphadoxine-pyrimethamine. The population pharmacokinetics of AQ and N-DEAQ were modeled using the non-linear mixed effects approach as implemented in NONMEM. Bayesian post-hoc estimates of individual pharmacokinetic parameters were used to generate individual profiles of N-DEAQ exposure. The correlation between N-DEAQ exposure and effect was studied in 212 patients and modeled with logistic regression in NONMEM. The pharmacokinetics of AQ and N-DEAQ were best described by two parallel two-compartment models with a central and a peripheral compartment for each compound. The systemic exposure to AQ was low in comparison to N-DEAQ. The t(1/2 lambda) of N-DEAQ ranged from 3 days to 12 days. There was a statistically significant, yet weak, association between N-DEAQ concentration on day 7 and treatment outcome. The age-based dosing schedule currently recommended in Zanzibar appeared to result in inadequate exposure to N-DEAQ in many patients.
Hietala
Sofia Friberg
SF
Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at Göteborg University, Box 431, Göteborg 405 30, Sweden.
Bhattarai
Achuyt
A
Msellem
Mwinyi
M
Röshammar
Daniel
D
Ali
Abdullah S
AS
Strömberg
Johan
J
Hombhanje
Francis W
FW
Kaneko
Akira
A
Björkman
Anders
A
Ashton
Michael
M
D000655:Amodiaquine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D000962:Antimalarials / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008954:Models, Biological
D000962:Antimalarials; D000655:Amodiaquine; C047386:desethylamodiaquine