Semimechanistic Pharmacokinetic and Pharmacodynamic Modeling of Piperaquine in a Volunteer Infection Study with Plasmodium falciparum Blood-Stage Malaria
Wattanakul T., Baker M., Mohrle J., McWhinney B., Hoglund RM., McCarthy JS., Tarning J.
<jats:title>ABSTRACT</jats:title> <jats:p>Dihydroartemisinin-piperaquine is a recommended first-line artemisinin combination therapy for <jats:named-content content-type="genus-species">Plasmodium falciparum</jats:named-content> 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 <jats:named-content content-type="genus-species">Plasmodium falciparum</jats:named-content> 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 PCR (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 <jats:named-content content-type="genus-species">P. falciparum</jats:named-content> malaria. Piperaquine-associated parasite killing was estimated using a maximum effect (<jats:italic>E</jats:italic><jats:sub>max</jats:sub>) 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<jats:sup>2</jats:sup> 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. (This study has been registered in the Australian and New Zealand Clinical Trials Registry under no. ANZCTRN12613000565741.)</jats:p>