Nicharee Jiracheep1, Kalayanee Chairat1, Richard Hoglund1,2, Joel Tarning1,2
1Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 2Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University
Introduction: Malaria is an infectious disease afflicting people primarily in developing countries. The World Health Organisation estimated a total of 246 million clinical cases and 569,000 deaths in 2023 [1]. Children under the age of 5 years bear the main burden of malaria. The treatment of malaria is threatened by artemisinin and partner-drug resistance in Southeast Asia and Africa, thus limiting the efficacy of current antimalarial combination therapies. Arterolane is a synthetic non-artemisinin trioxolane peroxide antimalarial compounds, which has shown an extended elimination half-life and a rapid parasiticidal activity [2,3]. It has been developed into a fixed-dose combination of arterolane and piperaquine in the treatment of uncomplicated P. falciparum malaria [4]. Most recently, novel triple combination therapies have been trialled, combining standard combination therapies with an additional partner drug to treat artemisinin-resistant infections. Objectives: This study aimed to characterise the population pharmacokinetic properties of arterolane and piperaquine when administered with and without mefloquine in Kenyan children with uncomplicated malaria. In addition, to assess and describe the relationship between antimalarial exposure and QT interval prolongation. The developed pharmacometric model was used to evaluate and select an optimal weight-based dosing regimen, facilitating the development of a novel fixed-dose triple antimalarial combination therapy. Methods: A total 145 of paediatric patients (age 2-12 years) were enrolled into this study, receiving either arterolane-piperaquine (n=73) or arterolane-piperaquine-mefloquine (n=72). Weight-based dosing, administered at 0, 24, and 48 hours was designed to achieve an arterolane dose of 4 mg/kg, a piperaquine dose of 20 mg/kg, and a mefloquine dose of 8 mg/kg of body weight. This approach aligns with the WHO’s recommended dosing guidelines [5]. Nonlinear mixed-effects modelling (NONMEM 7.5) was applied to characterise the pharmacokinetics of arterolane, piperaquine and mefloquine. Available covariates were evaluated, with a particular focus on the impact of drug-drug interactions, age, body weight and vomiting. QT prolongation was modelled using a conservative linear direct-effect model. Model-based simulations were conducted to evaluate dose adjustments aimed at optimising exposure across body weights (from 5-100 kg). Results: The pharmacokinetics of arterolane was best described by a one-compartment disposition model with two-transit absorption compartments, while piperaquine was best described by a three-compartment disposition model with two-transit absorption compartments. In addition, mefloquine was best described by two-compartment disposition with two-transit absorption compartment, while its metabolite carboxymefloquine was best described by one-compartment. Co-administration of mefloquine did not significantly alter arterolane or piperaquine exposure, nor was mefloquine exposure affected by concomitant administration of arterolane and piperaquine. Body weight was a significant covariate when implemented as an allometric function on all clearance and volume of distribution parameters. No significant difference in QTc prolongation was observed between standard treatment with arterolane-piperaquine and the novel triple combination treatment of arterolane-piperaquine-mefloquine. Simulations demonstrated that children at lower weights (<10 kg) showed lower antimalarial drug exposures compared to older, heavier children and adults. Model-based simulations suggested that current dosing may lead to suboptimal systemic exposures in younger children. Conclusions: This study successfully characterised the population pharmacokinetics of arterolane, piperaquine and mefloquine in Kenyan children. Body weight was the only significant covariate, and there was no increase in drug-associated QT prolongation when arterolane-piperaquine was co-administered with mefloquine, supporting the safety of this novel triple combination regimen in the treatment of uncomplicated malaria. Small children require higher weight-adjusted doses to achieve comparable exposure levels to older children or adults. The developed pharmacometric model was used to develop a practical weight-based dosing regimen for an equivalent drug exposure in all patient groups.
1. Organization, W.H., World malaria report 2024. 2024: World Health Organization. 2. Kim, H.S., J.T. Hammill, and R.K. Guy, Seeking the Elusive Long-Acting Ozonide: Discovery of Artefenomel (OZ439). J Med Chem, 2017. 60(7): p. 2651-2653. 3. Benakis, A., et al., Pharmacokinetics of artemisinin and artesunate after oral administration in healthy volunteers. The American journal of tropical medicine and hygiene, 1997. 56(1): p. 17-23. 4. Patil, C., et al., Fixed dose combination of arterolane and piperaquine: a newer prospect in antimalarial therapy. Ann Med Health Sci Res, 2014. 4(4): p. 466-71. 5. World Health Organization, 2015. Guidelines for the treatment of malaria. World Health Organization.
Reference: PAGE 33 (2025) Abstr 11483 [www.page-meeting.org/?abstract=11483]
Poster: Drug/Disease Modelling - Other Topics