Identifying an optimal dihydroartemisinin-piperaquine dosing regimen for malaria prevention in young Ugandan children

Nat Commun. 2021 Nov 18;12(1):6714. doi: 10.1038/s41467-021-27051-8.

Abstract

Intermittent preventive treatment (IPT) with dihydroartemisinin-piperaquine (DP) is highly protective against malaria in children, but is not standard in malaria-endemic countries. Optimal DP dosing regimens will maximize efficacy and reduce toxicity and resistance selection. We analyze piperaquine (PPQ) concentrations (n = 4573), malaria incidence data (n = 326), and P. falciparum drug resistance markers from a trial of children randomized to IPT with DP every 12 weeks (n = 184) or every 4 weeks (n = 96) from 2 to 24 months of age (NCT02163447). We use nonlinear mixed effects modeling to establish malaria protective PPQ levels and risk factors for suboptimal protection. Compared to DP every 12 weeks, DP every 4 weeks is associated with 95% protective efficacy (95% CI: 84-99%). A PPQ level of 15.4 ng/mL reduces the malaria hazard by 95%. Malnutrition reduces PPQ exposure. In simulations, we show that DP every 4 weeks is optimal across a range of transmission intensities, and age-based dosing improves malaria protection in young or malnourished children.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Algorithms
  • Antimalarials / administration & dosage
  • Antimalarials / pharmacokinetics
  • Antimalarials / therapeutic use
  • Artemisinins / administration & dosage
  • Artemisinins / pharmacokinetics
  • Artemisinins / therapeutic use*
  • Child
  • Child, Preschool
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Incidence
  • Infant
  • Malaria, Falciparum / drug therapy*
  • Malaria, Falciparum / epidemiology
  • Malaria, Falciparum / parasitology
  • Male
  • Models, Biological
  • Outcome Assessment, Health Care / methods
  • Outcome Assessment, Health Care / statistics & numerical data
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / physiology
  • Pregnancy
  • Pregnancy Complications, Parasitic / drug therapy*
  • Pregnancy Complications, Parasitic / metabolism
  • Quinolines / administration & dosage
  • Quinolines / pharmacokinetics
  • Quinolines / therapeutic use*
  • Uganda / epidemiology

Substances

  • Antimalarials
  • Artemisinins
  • Quinolines
  • artenimol
  • piperaquine

Associated data

  • ClinicalTrials.gov/NCT02163447