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.
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Authors | Sofia Friberg Hietala, Achuyt Bhattarai, Mwinyi Msellem, Daniel Röshammar, Abdullah S Ali, Johan Strömberg, Francis W Hombhanje, Akira Kaneko, Anders Björkman, Michael Ashton |
Journal | Journal of pharmacokinetics and pharmacodynamics
(J Pharmacokinet Pharmacodyn)
Vol. 34
Issue 5
Pg. 669-86
(Oct 2007)
ISSN: 1567-567X [Print] United States |
PMID | 17620000
(Publication Type: Journal Article)
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Chemical References |
- Antimalarials
- Amodiaquine
- desethylamodiaquine
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Topics |
- Amodiaquine
(analogs & derivatives, pharmacokinetics)
- Antimalarials
(pharmacokinetics)
- Child
- Child, Preschool
- Humans
- Infant
- Malaria, Falciparum
(drug therapy)
- Models, Biological
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