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Population pharmacokinetics of amodiaquine and desethylamodiaquine in pediatric patients with uncomplicated falciparum malaria.

Abstract
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.
AuthorsSofia Friberg Hietala, Achuyt Bhattarai, Mwinyi Msellem, Daniel Röshammar, Abdullah S Ali, Johan Strömberg, Francis W Hombhanje, Akira Kaneko, Anders Björkman, Michael Ashton
JournalJournal of pharmacokinetics and pharmacodynamics (J Pharmacokinet Pharmacodyn) Vol. 34 Issue 5 Pg. 669-86 (Oct 2007) ISSN: 1567-567X [Print] United States
PMID17620000 (Publication Type: Journal Article)
Chemical References
  • Antimalarials
  • Amodiaquine
  • desethylamodiaquine
Topics
  • Amodiaquine (analogs & derivatives, pharmacokinetics)
  • Antimalarials (pharmacokinetics)
  • Child
  • Child, Preschool
  • Humans
  • Infant
  • Malaria, Falciparum (drug therapy)
  • Models, Biological

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