Pharmacokinetic analysis supports improvements to antimalarial dosing regimens

Although huge gains have been made against malaria infection over the past decade, malaria still kills more than 1,200 people every day – primarily children under the age of five in sub-Saharan Africa.

Dihydroartemisinin-piperaquine (DP) is a widely used antimalarial and one of the first-line treatments against malaria recommended by the World Health Organization (WHO). However, dosing recommendations from manufacturers were developed before there was extensive pharmacokinetic data of piperaquine use in young children. Previous studies have suggested that based on these dosing recommendations, young children with malaria are being under-dosed.

In the largest study of its kind, a team of researchers led by WWARN and the Mahidol-Oxford Research Unit in Bangkok, Thailand have developed a pharmacokinetic model that enabled a revised dose regimen to safely treat all malaria patients with DP, including young children. Results from this study, published this week in PLOS Medicine, have already been used by the WHO expert review panel’s decision to update the Guidelines for the treatment of malaria.

“It’s crucial to develop optimised dosing regimens to ensure appropriate drug exposure in all patient groups” says Prof Joel Tarning, senior author of the study and Head of Pharmacometrics at WWARN. “This revised dose regimen of dihydroartemisinin-piperaquine is intended to provide equivalent piperaquine exposures safely in all patients, including in small children with malaria. It presents an important step towards giving all patients an equal chance of cure.”

The team collated drug concentration data from 728 malaria patients in 11 separate clinical trials. The pharmacokinetic model was developed to describe the pharmacokinetic properties of piperaquine, the expected variability between patients, and the influence of biologically important covariates.

Using this model, the team were able to demonstrate that young children and heavier adults had a substantially lower piperaquine exposure after the industry-based dose recommendations were used. This under exposure might increase the risk of treatment failures. The model was then used to derive a new optimised dose regimen that would sufficiently treat all populations, including vulnerable groups such as young children.

“An optimised dose regimen should prolong the useful therapeutic life of dihydroartemisinin-piperaquine by not just increasing cure rates, but hopefully also slowing the development of antimalarial drug resistance – a major threat in Southeast Asia where resistance is confirmed and likely to spread or emerge beyond the Greater Mekong regional borders,” adds Dr Richard Hoglund, first author of the study from the Mahidol-Oxford Research Unit and WWARN.

This study builds on the WWARN DP Dose Impact Study which, published in 2013, found that DP is still overall a highly efficacious drug. However, the study also highlighted that even when the recommended dose was given, children under five years had a higher risk of treatment failure.

“It is essential that current antimalarials like dihydroartemisinin-piperaquine remain effective for as long as possible while we work on new treatment medicines,” says Dr Steve Kern, Deputy Director of Quantitative Sciences at the Bill and Melinda Gates Foundation. “Evidence emanating from these analyses in 2013 and 2016 are critical in providing the global health community with necessary information to adjust our approaches to treating malaria with this combination effectively.”

The WWARN Pharmacology Group continue to provide research results to improve dosing regimens in patient populations, particularly for vulnerable groups such as small children and pregnant women. Similar PK analyses are under way to investigate inadequate drug exposure and inform antimalarial dosage for such treatments as lumefantrine, amodiaquine, pyrimethamine and sulfadoxine.

Find out more about the WWARN Pharmacology and Pharmacometric Groups.

Publication details:

Hoglund R, et al. Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-analysis. PLOS Medicine. January 2016. http://dx.doi.org/10.1371/journal.pmed.1002212