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Piperaquine PK/PD Study Group

An analysis of pooled individual patient PK/PD data to inform pipeaquine dosing recommendations and use in key target populations.

Update and Overview

The population pharmacokinetic-pharmacodynamic (PK/PD) analysis of the Piperaquine PK/PD Study Group is complete. The outcomes were circulated among participating investigators for feedback and approval.

In the pharmacokinetic analysis ,data from a total of 571 patients and 50 healthy volunteers, from Africa (n=365) and South East Asia (n=256) is included.

The Study Group data curation was completed in 2013. Published in 2017.

Rationale

Dihydroartemisinin-piperaquine (DHA-PPQ) is a fixed dose artemisinin-based combination therapy recently added to the list of WHO recommended treatments for uncomplicated malaria. Despite an increase in DHA-PPQ use, the drug exposure required to provide a high cure rate and/or a reasonable period of post-treatment prophylaxis is not yet clearly defined.

The urgency of this pooled individual patient PK-PD analysis was highlighted by the publication of the WWARN dihydroartemisinin-piperaquine dose impact study group results in December 2013 which demonstrates that (DHA-PPQ) has excellent efficacy in a wide range of transmission settings; however, low piperaquine dosing is associated with treatment failure. A larger proportion of young children receive a low dose of piperaquine and young children are also at increased risk of treatment failures, even after adjusting for dose and parasitemia, emphasising the need for further dose optimisation.

Objectives

  • Refine the definition of piperaquine therapeutic concentrations, both in terms of the pharmacokinetic parameter (e.g. AUC and day 7 concentration) that provides the best predictor of therapeutic response
  • Determine patient and environmental factors that cause changes in piperaquine pharmacokinetics substantial enough to compromise efficacy (and safety, if data permitting)

Inclusion criteria for data sets

  • Patients with P. falciparum or healthy volunteers
  • Treated with dihydroartemisinin and piperaquine
  • Drug concentration(s) of piperaquine.

Data standardisation and analysis

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

The pooled piperaquine PK/PD database included the following:

  • Demographics
  • Baseline patient characteristics 
  • Clinical signs and symptoms over time
  • Dosing (mg/kg dose) and dosing time(s)
  • Piperaquine 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 contribute relevant data sets to the pooled analysis. Data sets remain the property of the investigator. The Study Group collectively made 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 Dr Joel Tarning, Head of the Pharmacometric Modelling Unit of WWARN. Richard Höglund lead the pharmacometric analysis. Lesley Workman lead the data curation. These individuals coordinated activities including the completion of data collection, plans for analysis, and drafting of publications and reports for group review.

Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis. Hoglund RM, Workman L, Edstein MD, Thanh NX, Quang NN, Zongo I, Ouédraogo JB, Borrmann S, Mwai L, Nsanzabana C, Price RN, Dahal P, Sambol NC, Parikh S, Nosten F, Ashley EA, Phyo AP, Lwin KM, McGready R, Day NP, Guerin PJ, White NJ, Barnes KI, Tarning J. PLOS Medicine, 2017; eCollection: 14(1). Doi: 10.1371/journal.pmed.1002212  PMID: 28072872

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

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