Rethinking Dosing Regimen Selection of Piperaquine for Malaria Chemoprevention: A Simulation Study

The combination of short-acting dihydroartemisinin and long-acting piperaquine (DP) is among the first-line therapies for the treatment of uncomplicated Plasmodium falciparum malaria. Population pharmacokinetic models of piperaquine (PQ) based on data from acute treatment of young children can be used to predict exposure profiles of piperaquine under different DP chemoprevention regimens. The purpose of our study was to make such predictions in young children.

Based on a prior population pharmacokinetic model of PQ in young Ugandan children, we simulated capillary plasma concentration-time profiles (including their variability) of candidate chemoprevention regimens for a reference population of 1-2 year olds weighing at least 11 kg. Candidate regimens that were tested included monthly administration of standard therapeutic doses, bimonthly dosing, and weekly dosing (with and without a loading dose).

Once daily doses of 320 mg for three days (960 mg total) at the beginning of each month are predicted to achieve an average steady-state trough capillary piperaquine concentration of 35 ng/mL, with 60% achieving a level of 30 ng/mL or higher. In contrast, weekly dosing of 320 mg (i.e., 33% higher amount per month) is predicted to approximately double the average steady-state trough concentration, increase the percent of children predicted to achieve 30 ng/mL or higher (94%), while at the same time lowering peak concentrations. Exposure at steady-state, reached at approximately 3 months of multiple dosing, is expected to be approximately 2-fold higher than exposure following initial dosing, due to accumulation. A loading dose improves early exposure, thereby reducing the risk of breakthrough infections at the initiation of chemoprevention.

Once weekly chemoprevention of DP predicts favourable exposures with respect to both trough and peak concentrations. These predictions need to be verified, as well as safety evaluated, in field-based clinical studies of young children. Simulations based on prior knowledge provide a systematic information-driven approach to evaluate candidate DP chemopreventive regimens for future trial designs.