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

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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 1/2λ 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 and Affiliations

  1. Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at Göteborg University, Box 431, Göteborg, 405 30, Sweden

    Sofia Friberg Hietala, Daniel Röshammar & Michael Ashton

  2. Malaria Research Unit, Unit for Infectious Diseases, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden

    Achuyt Bhattarai, Johan Strömberg, Akira Kaneko & Anders Björkman

  3. Zanzibar Malaria Control Program, Zanzibar, Tanzania

    Mwinyi Msellem & Abdullah S. Ali

  4. Department of International Affairs and Tropical Medicine, Tokyo Women’s Medical University, Tokyo, Japan

    Akira Kaneko

  5. Faculty of Health Sciences, Divine Word University, Madang, Papua New Guinea

    Francis W. Hombhanje

Authors
  1. Sofia Friberg Hietala
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  2. Achuyt Bhattarai
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  3. Mwinyi Msellem
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  4. Daniel Röshammar
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  5. Abdullah S. Ali
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  6. Johan Strömberg
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  7. Francis W. Hombhanje
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  8. Akira Kaneko
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  9. Anders Björkman
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  10. Michael Ashton
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Corresponding author

Correspondence to Michael Ashton.

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Hietala, S.F., Bhattarai, A., Msellem, M. et al. Population pharmacokinetics of amodiaquine and desethylamodiaquine in pediatric patients with uncomplicated falciparum malaria. J Pharmacokinet Pharmacodyn 34, 669–686 (2007). https://doi.org/10.1007/s10928-007-9064-2

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  • DOI: https://doi.org/10.1007/s10928-007-9064-2

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