Nada Abla (1), Lisa Almond (2), Maurice Dickins (2), Nathalie Gobeau (1), Susan A. Charman (3), Karen Rowland-Yeo (2), Zoe Barter (2), Jörg Möhrle (1), Jeremy Burrows (1) and David Wesche (4)(5)
(1) Medicines for Malaria Venture, Geneva, Switzerland (2) Simcyp Limited (a Certara Company), Sheffield, UK, (3) Monash University, Australia, (4) Bill & Melinda Gates Foundation, Seattle, USA, (5) Great Lakes Drug Development (a Certara Company), Grand Rapids, USA
Introduction: In 2016, an estimated 216 million cases of malaria occurred worldwide, with an estimated 445 000 deaths. The current WHO recommendation for the treatment of uncomplicated falciparum malaria is artemisinin-based combination therapies (ACTs) [1]. Different ACTs are available and a better understanding of the pharmacokinetic behavior and potential interactions of each individual drug is needed in order to optimize the doses for new combinations of two or more drugs, and potentially adapt the doses in children, who receive sub-optimal doses in some cases [2].
Objectives: To develop PBPK models for the major antimalarial compounds currently in use and make them publicly available to researchers to support the development of new combinations, possibly including up to three antimalarials, and the dose optimization of existing combinations in children.
Methods: The following in vitro and physicochemical data were generated for all compounds at the Centre for Drug Candidate Optimisation, Monash University, Australia: Log D 7.4, pKa, apparent permeability and efflux ratio in Caco-2 cells, plasma protein binding, blood to plasma ratio, fraction unbound in microsomes, intrinsic clearance in human liver microsomes, aqueous solubility at pH 7.4, solubility in FaSSIF, FeSSIF and FaSSGF, direct CYP inhibition. CYP and UGT reaction phenotyping data were generated for selected compounds at Cyprotex when not available. These data were used as initial input parameters for building PBPK models for 16 marketed antimalarial drugs using Simcyp software (a Certara Company, Sheffield, UK). Available clinical data for these marketed compounds were included to further optimize the models. Victim and perpetrator properties of each compound were included based on in vitro data or pivotal drug-drug interaction studies, when available.
Results: Models were developed for 16 drugs: mefloquine, dihydroartesunate (DHA), lumefantrine, pyronaridine, primaquine (and its metabolite carboxyprimaquine), piperaquine, amodiaquine (and its metabolite desethylamodiaquine), atovaquone, proguanil (and its metabolite cycloguanil), artemether, chloroquine, azithromycin, doxycycline, pyrimethamine, quinine, and sulfadoxine. The model development followed the following workflow: an initial model was built using in vitro DMPK and physicochemical data, it was then evaluated and refined using clinical pharmacokinetic and drug-drug interaction data, when available, and finally verified using an independent clinical data set. Models may be applied as victim and perpetrator to understand drug-drug interaction potential via simulations, except models for atovaquone, azithromycin, lumefantrine, and pyrimethamine which can be used as perpetrators in DDI simulations only until information on elimination routes becomes available.
Conclusion: PBPK models for 16 antimalarial drugs are ready to be shared with researchers in the malaria field who are interested in using them for different applications. These models can be made available on request. This is the first step of an effort to develop open-source PBPK models for antimalarial compounds. The next step will focus on compounds in different stages of the research and development pipeline, to support the development of new combination therapies for malaria.
References:
[1] WHO. World Malaria Report 2017. Geneva, World Health Organization, 2017.
[2] Hoglund RM et al. Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis. PLoS Med. 2017 Jan10;14(1)
Reference: PAGE 27 (2018) Abstr 8651 [www.page-meeting.org/?abstract=8651]
Poster: Methodology - Other topics