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Amodiaquine PK/PD Study Group

An analysis of pooled individual patient PK/PD data to provide the necessary evidence to identify cases of inadequate drug exposure, and inform recommendations on dosage and use in key target populations.

Update and overview

The Amodiaquine Pharmacokinetic/Pharmacodynamic (PK/PD) Study Group has finished gathering and curating data shared with WWARN by participating investigators. Data from 1029 patients with a total of 896 amodiaquine and 2669 desethyl-amodiaquine concentrations were curated to a standard format and appended to the pooled dataset. 

Rationale

Amodiaquine is a recommended treatment for uncomplicated malaria (in combination with artesunate) and is being evaluated for use as intermittent preventive treatment. However, the drug exposure of amodiaquine and of its active metabolite desethylamodiaquine required to provide a high cure rate and a reasonable period of post-treatment prophylaxis are not yet clearly defined. 

Lower day 7 desethylamodiaquine concentrations have been associated with an increased risk of treatment failure.1,2  Although limited data is currently reported on the factors that alter drug exposure, it has been shown that concomitant efavirenz administration increases the risk of toxicity substantially.3 

Objective

  • Refine the definition of amodiaquine (desethylamodiaquine) therapeutic concentrations
  • Determine patient factors that cause changes in amodiaquine pharmacokinetics that are substantial enough to compromise efficacy

Inclusion criteria for data sets

  • Patients with or at risk of P falciparum or healthy volunteers;
  • Treated with amodiaquine and/or artesunate-amodiaquine and/or amodiaquine-SP; and,
  • Drug concentration(s) of amodiaquine and/or desethylamodiaquine.

Data standardisation and analysis

After upload to the WWARN Data Repository, data sets were transformed, standardised and pooled according to the WWARN Pharmacology and Clinical Groups’ Data Management and Statistical Analysis Plans. The statistician appointed to the project will develop a statistical analysis plan specifically for the pooled analysis, in collaboration with Study Group members.

The pooled amodiaquine PK/PD database will include the following:

  • Demographics 
  • Baseline patient characteristics
  • Clinical signs and symptoms over time
  • Dosing (mg/kg dose and dosing times)
  • Amodiaquine (desethylamodiaquine) concentration(s) and sample time(s)
  • Parasite densities over time
  • Treatment outcome (including PCR, if available)
  • Haematology (biochemistry)
  • Molecular data

Study Group governance and membership

The Study Group comprised participating investigators who contributed relevant data sets to the pooled analysis. Data sets remain the property of the investigator. The Study Group collectively makes decisions with respect to including additional studies, data analysis and plans for publication, in line with the WWARN Publication Policy. The Study Group was led by Professor Karen Barnes, Head of WWARN Pharmacology Group, and the analysis was supervised by Dr Paolo Denti Head of the Pharmacometric Unit at the University of Cape Town. Together they coordinated activities including the completion of data collection, analysis planing, and finalising publications and reports for group review.

For further information, email Karen Barnes karen [dot] barnes [at] wwarn [dot] org.

References

1 Stepniewska K et al (2009). Population pharmacokinetics of artesunate and amodiaquine in African children. Malaria Journal, 8:200.

2 Hietala SF et al (2007). Population pharmacokinetics of amodiaquine and desethylamodiaquine in pediatric patients with uncomplicated falciparum malaria. Journal of Pharmacokinetics and Pharmacodynamics,34:669-686.

3 German P, et al (2007). Hepatotoxicity due to a drug interaction between amodiaquine plus artesunate and efavirenz. Clin Infect Dis; 44(6):889-91.