Project: Improving the impact of existing Malaria Products - ACTs

Acronym IMPACT (Reference Number: EDCTP-CSA-2014-282)
Duration 01/01/2016 - 31/12/2017
Project Topic The antimalarial dihydroartemisinin-piperaquine (DHA-PPQ) is highly efficacious against uncomplicated malaria. Due to its long half-life and associated chemoprophylactic effect, DHA-PPQ is also considered the most promising antimalarial for drug-based transmission reduction efforts, such as mass drug administration. Widespread use of an antimalarial among unselected populations that includes asymptomatic and uninfected individuals requires a drug with a wide therapeutic dose range and excellent safety profile.However, DHA-PPQ has a relatively narrow, poorly defined therapeutic dose range which poses dosing challenges. There is emerging evidence that young children are being underdosed. It is also unclear whether PPQ concentration dependent cardiac QTc prolongation poses a clinical risk for specific subgroups. This uncertainty about the exact safe upper PPQ concentration threshold and recognition of the vulnerability of children has led WHO to consider a complex weight-based regimen. This hampers DHA-PPQ’s safe and effective introduction into national control programmes and has limited optimization of dosing to prolong its effective lifespan. It also highlights the urgent need to standardize dose optimization process. OBJECTIVES: (1) To determine the frequency and severity of PPQ cardio-toxicity, and its correlation with dose and drug concentration. (2) Use these findings to update the upper PPQ dose thresholds (across key risk groups) and identify remaining research priorities. (3) To review DHA-PPQ dosing challenges so far, lessons learnt, and opportunities to address these through a more standardized process for antimalarial dose optimization. (4) To raise awareness of dose optimization research priorities among researchers, funders and control programmes. WORKPLAN: We plan to conduct pooled patient-level pharmacokinetic-pharmacodynamic safety analyses of DHA-PPQ cardiotoxicity and antiretroviral drug interactions using all available data (including the EDCTP funded targeted safety studies ADAPT and ADJusT). The analyses will use two pioneering data sharing platforms on antimalarial efficacy and safety, developed by WWARN and LSTM. Findings will be incorporated into the recent evidence review of the 2015 WHO Malaria Treatment Guidelines dosing task force to inform dosing regimen recommendations. Lessons learnt and research priorities will be identified and used for targeted advocacy activities. IMPACT: The proposed work will guide policy decisions on DHA-PPQ dosing regimens. Beyond DHA-PPQ, it will demonstrate the importance of identifying global research priorities for targeted antimalarial safety studies and of integrating pooled individual level safety analyses into WWARN’s global efficacy data platform. Linking efficacy and safety data offers a powerful standardized process for dose optimization that is applicable across a range of drugs.
Website visit project website
Network EDCTP2
Call Maximising the impact of EDCTP research: translation of research results into policy and practice

Project partner

Number Name Role Country
1 Liverpool School of Tropical Medicine Partner United Kingdom
2 The Chancellor, the Masters and the Scholars of the University of Oxford Partner United Kingdom
3 University of Malawi, College of Medicine Partner Malawi
4 University of Cape Town Partner South Africa