Journal of Pharmacokinetics and Pharmacodynamics

, Volume 34, Issue 5, pp 669–686 | Cite as

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

  • Sofia Friberg Hietala
  • Achuyt Bhattarai
  • Mwinyi Msellem
  • Daniel Röshammar
  • Abdullah S. Ali
  • Johan Strömberg
  • Francis W. Hombhanje
  • Akira Kaneko
  • Anders Björkman
  • Michael Ashton
Article

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 t1/2λ 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.

Keywords

Amodiaquine Desethylamodiaquine Malaria Child Population pharmacokinetic/pharmacodynamic modeling 

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Sofia Friberg Hietala
    • 1
  • Achuyt Bhattarai
    • 2
  • Mwinyi Msellem
    • 3
  • Daniel Röshammar
    • 1
  • Abdullah S. Ali
    • 3
  • Johan Strömberg
    • 2
  • Francis W. Hombhanje
    • 5
  • Akira Kaneko
    • 2
    • 4
  • Anders Björkman
    • 2
  • Michael Ashton
    • 1
  1. 1.Unit for Pharmacokinetics and Drug Metabolism, Department of PharmacologySahlgrenska Academy at Göteborg UniversityGöteborgSweden
  2. 2.Malaria Research Unit, Unit for Infectious Diseases, Department of MedicineKarolinska University HospitalStockholmSweden
  3. 3.Zanzibar Malaria Control ProgramZanzibarTanzania
  4. 4.Department of International Affairs and Tropical MedicineTokyo Women’s Medical UniversityTokyoJapan
  5. 5.Faculty of Health SciencesDivine Word UniversityMadangPapua New Guinea

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