Semimechanistic Pharmacokinetic and Pharmacodynamic Modeling of Piperaquine in a Volunteer Infection Study with Plasmodium falciparum Blood-Stage Malaria

Dihydroartemisinin-piperaquine is a recommended first-line artemisinin combination therapy for Plasmodium falciparum malaria. Piperaquine is also under consideration for other antimalarial combination therapies. The aim of this study was to develop a pharmacokinetic-pharmacodynamic model that might be useful when optimizing the use of piperaquine in new antimalarial combination therapies. The pharmacokinetic-pharmacodynamic model was developed using data from a previously reported dose-ranging study where 24 healthy volunteers were inoculated with 1,800 blood-stage Plasmodium falciparum parasites. All volunteers received a single oral dose of piperaquine (960 mg, 640 mg, or 480 mg) on day 7 or day 8 after parasite inoculation in separate cohorts. Parasite densities were measured by quantitative KR (qPCR), and piperaquine levels were measured in plasma samples. We used nonlinear mixed-effect modeling to characterize the pharmacokinetic properties of piperaquine and the parasite dynamics associated with piperaquine exposure. The pharmacokinetics of piperaquine was described by a three-compartment disposition model. A semimechanistic parasite dynamics model was developed to explain the maturation of parasites, sequestration of mature parasites, synchronicity of infections, and multiplication of parasites, as seen in natural clinical infections with P. falciparum malaria. Piperaquine-associated parasite killing was estimated using a maximum effect (E-max) function. Treatment simulations (i.e., 3-day oral dosing of dihydroartemisinin-piperaquine) indicated that to be able to combat multidrug-resistant infections, an ideal additional drug in a new antimalarial triple-combination therapy should have a parasite reduction ratio of >= 10(2) per life cycle (38.8 h) with a duration of action of >= 2 weeks. The semimechanistic pharmacokinetic-pharmacodynamic model described here offers the potential to be a valuable tool for assessing and optimizing current and new antimalarial drug combination therapies containing piperaquine and the impact of these therapies on killing multidrug-resistant infections.

Automated summary

Dihydroartemisinin-piperaquine is commonly used as a first-line treatment for Plasmodium falciparum malaria, and this study aimed to develop a pharmacokinetic-pharmacodynamic model to optimize its use in new antimalarial combination therapies. By analyzing data from healthy volunteers, the study characterized the pharmacokinetic properties of piperaquine and developed a semimechanistic parasite dynamics model related to piperaquine exposure. Treatment simulations suggested that an ideal additional drug in new antimalarial triple-combination therapies should have specific parasite reduction ratios and durations to combat multidrug-resistant infections effectively.