Thanaporn Wattanakul (1), Mark Baker (2), Joerg J. Möhrle (3), Brett McWhinney (4), Richard M. Hoglund (1,5), James S. McCarthy (6,7), Joel Tarning (1,5)
(1) Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, (2) Department of Clinical Pharmacology, ViiV Healthcare, Geneva, Switzerland (3) Medicine for Malaria Venture, Meyrin, Switzerland, (4) Analytical Chemistry Unit, Pathology Queensland, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia, (5) Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom, (6) QIMR Berghofer Medical Research Institute, Brisbane, Australia, (7) School of Medicine, The University of Queensland, Brisbane, QLD, Australia
Objectives: Dihydroartemisinin-piperaquine is a recommended first-line artemisinin combination therapy for Plasmodium falciparum malaria. Piperaquine is also under consideration for other antimalarial combination therapies. Understanding the in vivo pharmacokinetic-pharmacodynamic properties of drugs are essential for rational dose-optimization and dose-selection and induced blood-stage malaria infection studies are ideal to characterize these properties for antimalarial drugs. The aim of this study was to develop a pharmacokinetic-pharmacodynamic model describing piperaquine and its parasite dynamics in healthy volunteers with induced Plasmodium falciparum blood-stage malaria that might be useful when optimizing the use of piperaquine in new antimalarial combination therapies.
Methods: 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 (960mg, 640mg, or 480mg) on day 7 or day 8 after parasite inoculation in separate cohorts. Plasma concentrations of piperaquine were measured using liquid chromatography and mass spectrometry. Densely collected plasma samples were collected before piperaquine administration; after piperaquine administration for up to 18 days after treatment; and at the end of study (day 28 for cohorts 1 and 2, day 37 for cohort 3a, and day 35 for cohort 3b). Parasite densities were measured by quantitative PCR (qPCR). This study has been registered in the Australian and New Zealand Clinical Trials Registry under no. ANZCTRN12613000565741. We used nonlinear mixed-effect modeling to characterize the pharmacokinetic properties of piperaquine, the parasite dynamics before drug administration (i.e. natural parasite growth), and the parasite dynamics associated with piperaquine exposure. Pharmacokinetic and pharmacodynamic parameters were estimated using the FOCE-I and the FOCE-I with the Laplacian method, respectively.
Results: The pharmacokinetics of piperaquine was described by a three-compartment disposition model. A semi-mechanistic 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 Plasmodium falciparum malaria. Piperaquine-associated parasite killing was estimated using a maximum effect (Emax) function. Treatment simulations (i.e., 3-day oral dosing) indicated that to be able to effectively combat multidrug-resistant infections, an additional antimalarial drug should be added to dihydroartemisinin-piperaquine. The simulations showed that the ideal drug to add to this new antimalarial triple-combination therapy should have a parasite reduction ratio of ≥102 per life cycle (38.8 h) with a duration of action of ≥2 weeks.
Conclusions: The semi-mechanistic 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.
References:
[1] Wattanakul T, Baker M, Mohrle J, McWhinney B, Hoglund RM, McCarthy JS, Tarning J. Semi-mechanistic pharmacokinetic and pharmacodynamic modeling of piperaquine in a volunteer infection study with Plasmodium falciparum blood-stage malaria. Antimicrobial agents and chemotherapy. 2021.
Reference: PAGE 29 (2021) Abstr 9725 [www.page-meeting.org/?abstract=9725]
Poster: Drug/Disease Modelling - Infection