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

• Published in: Journal of pharmacokinetics and pharmacodynamics Vol. 34; no. 5; pp. 669 - 686
• Main Authors: Hietala, Sofia Friberg, Bhattarai, Achuyt, Msellem, Mwinyi, Röshammar, Daniel, Ali, Abdullah S, Strömberg, Johan, Hombhanje, Francis W, Kaneko, Akira, Björkman, Anders, Ashton, Michael
• Format: Journal Article
• Language: English
• Published: United States Springer Nature B.V 01.10.2007
• Subjects: Amodiaquine - analogs & derivatives; Amodiaquine - pharmacokinetics; Antimalarials - pharmacokinetics; Child; Child, Preschool; children; combination; disposition; Farmaceutisk vetenskap; farmakokinetik malaria; Fysiologi; Humans; in-vitro; Infant; Malaria, Falciparum - drug therapy; Medicin och hälsovetenskap; metabolite; Models, Biological; nonmem; Pharmaceutical Sciences; Physiology; plasmodium-falciparum; regimens
• ISSN: 1567-567X; 1573-8744
• DOI: 10.1007/s10928-007-9064-2

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.