Semi-mechanistic pharmacokinetic and pharmacodynamic modelling 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:p>Dihydroartemisinin-piperaquine is a recommended first-line artemisinin combination therapy for <jats:italic>falciparum</jats:italic> malaria. Piperaquine is also under consideration for other antimalarial combination therapies. The aim of this study was to develop a pharmacokinetic-pharmacodynamic model that could be used to optimize 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 1,800 blood-stage <jats:italic>Plasmodium falciparum</jats:italic> 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 qPCR, and piperaquine levels were measured in plasma samples. We used nonlinear mixed-effect modelling to characterize the pharmacokinetic properties of piperaquine and the parasite dynamics associated with piperaquine exposure. Pharmacokinetics of piperaquine was described by a three-compartment disposition model. A semi-mechanistic parasite dynamics model was developed to explain maturation of parasites, sequestration of mature parasites, synchronicity of infections, and multiplication of parasites, as seen in natural clinical infections with <jats:italic>falciparum</jats:italic> malaria. Piperaquine-associated parasite killing was estimated using a maximum effect (E<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 semi-mechanistic pharmacokinetic-pharmacodynamic model described here offers the potential to be a valuable tool to assess and optimize current and new antimalarial drug combinations therapies containing piperaquine, and the impact of these therapies on killing multidrug resistant infections.</jats:p>