Malaria medication

SP 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 Sulfadoxine-Pyrimethamine (SP) Pharmacokinetic/Pharmacodynamic (PK/PD) Study Group has finished gathering and curating data shared with WWARN by participating investigators, and the analysis is ongoing. Data from seven countries in Africa has been curated and included in the pooled analysis dataset. To date, data from 1,240 individuals (1,065 malaria patients and 175 at risk of P. falciparum malaria) have been included with a total of 8,229 pyrimethamine and 8,238 sulfadoxine concentrations. Preliminary PK/PD results will be shared with the Study Group in Q2 2017.

Rationale

Sulfadoxine-Pyrimethamine (SP) is an intermittent preventive treatment in high-risk populations, such as pregnant women. In the few areas where it remains effective, it can be used in combination with artesunate for the treatment of uncomplicated malaria. However, the drug exposure of sulfadoxine and pyrimethamine required to provide a high cure rate and a reasonable period of post-treatment prophylaxis are not yet clearly defined. The highly synergistic relationship between sulfadoxine and pyrimethamine has made defining therapeutic concentrations particularly challenging for SP. The plasma concentrations of sulfadoxine and pyrimethamine in children aged 2–5 years were found to be significantly lower than in adults, while variable differences in pharmacokinetic parameters between pregnant and non-pregnant women have been observed.  

Objectives

  • Refine the definition of sulfadoxine-pyrimethamine therapeutic concentrations
  • Determine patient factors that cause changes in sulfadoxine-pyrimethamine pharmacokinetics substantial enough to compromise efficacy 

Inclusion criteria for data sets

  • Patients with or at risk of P. falciparum malaria or healthy volunteers;
  • Treated with sulfadoxine-pyrimethamine; and,
  • Drug concentration(s) of sulfadoxine and or pyrimethamine measured.

Data standardisation and analysis

After upload to the WWARN Data Repository, data sets will be transformed, standardised and pooled according to the WWARN Pharmacology and Clinical 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 sulfadoxine-pyrimethamine PK/PD database will include the following:

  • Demographics 
  • Baseline patient characteristics 
  • Clinical signs and symptoms over time 
  • Dosing (mg/kg dose) and dosing time(s)
  • Sulfadoxine and or pyrimethamine 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 comprises participating investigators who contribute relevant data sets to the pooled analysis. Data sets remain the property of the investigator. The Study Group is led by Professor Karen Barnes, Head of WWARN Pharmacology Group, the analysis is being supervised by Dr Paolo Denti Head of the Pharmacometrics Unit at the University of Cape Town. The study group collectively makes decisions with respect to data analysis and plans for publication, in line with the WWARN Publication Policy. These individuals will coordinate activities including the completion of data collection, plans for analysis, and drafting of publications and reports for group review.

For further information, email Karen Barnes (karen [dot] barnes [at] wwarn [dot] org (karen.barnes(at)wwarn.org)) or Lesley Workman (lesley [dot] workman [at] wwarn [dot] org (lesley.workman(at)wwarn.org)). 

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