Characterization of an in vivo concentration-effect relationship for piperaquine in malaria chemoprevention

Abstract

A randomized, placebo-controlled trial conducted on the northwest border of Thailand compared malaria chemoprevention with monthly or bimonthly standard 3-day treatment regimens of dihydroartemisinin-piperaquine. Healthy adult male subjects (N = 1000) were followed weekly during 9 months of treatment. Using nonlinear mixed-effects modeling, the concentration-effect relationship for the malaria-preventive effect of piperaquine was best characterized with a sigmoidal Emax relationship, where plasma concentrations of 6.7 ng/ml [relative standard error (RSE), 23%] and 20 ng/ml were found to reduce the hazard of acquiring a malaria infection by 50% [that is, median inhibitory concentration (IC50)] and 95% (IC95), respectively. Simulations of monthly dosing, based on the final model and published pharmacokinetic data, suggested that the incidence of malaria infections over 1 year could be reduced by 70% with a recently suggested dosing regimen compared to the current manufacturer's recommendations for small children (8 to 12 kg). This model provides a rational framework for piperaquine dose optimization in different patient groups.

Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis

“…Several studies have investigated the pharmacokinetic properties of piperaquine [6,10,23–25,27,29,30,32,35,40,58–60]. However, the present study is, to our knowledge, the largest analysis to date, incorporating data from 8,776 pharmacokinetic samples from 728 individuals from different target populations and continents.…”

Lumefantrine and Desbutyl-Lumefantrine Population Pharmacokinetic-Pharmacodynamic Relationships in Pregnant Women with Uncomplicated Plasmodium falciparum Malaria on the Thailand-Myanmar Border

“…New malaria infections were modeled using a constant hazard model with interval censoring. The interval was based on observed parasitemia at detection and the back-calculated plausible interval of parasite release from the liver (hepatic schizogony) by using fixed high (10-fold increase in parasitemia every 48 h, with the assumption of 10 5 parasites released from the liver) and low (5-fold increase in parasitemia every 48 h, 10 4 parasites released from the liver) multiplication rates ( 26 ). Consequently, an event represents the appearance of asymptomatic malaria instead of the time of microscopy detection (symptomatic malaria), which could be potentially later due to travel time to the hospital and/or disregarding of the symptoms by the patient.…”

Safety, Pharmacokinetics, and Mosquito‐Lethal Effects of Ivermectin in Combination With Dihydroartemisinin‐Piperaquine and Primaquine in Healthy Adult Thai Subjects

“…In recent years, mass drug administrations (MDAs) using the artemisinin‐based combination therapy (ACT) dihydroartemisinin‐piperaquine with primaquine have been evaluated throughout the GMS . Dihydroartemisinin rapidly clears Plasmodium ‐infected individuals of the majority of their asexual parasites, and piperaquine eliminates the residuum to prevent recrudescent infections while providing post‐treatment prophylaxis for ~ 1 month, which prevents new blood stage infections . Single low‐dose primaquine is added to kill late‐stage gametocytes and prevent onward transmission from infected individuals to Anopheles mosquitoes .…”