This submission belongs to the symposium “Pharmacometric approaches in malaria research”.
Introduction: Malaria is an infectious disease afflicting people primarily in developing countries. The World Health Organisation estimated 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, thus limiting the efficacy of current antimalarial therapies. Arterolane is a synthetic non‑artemisinin trioxolane peroxide antimalarial, which has shown an extended elimination half-life and a rapid parasiticidal activity [2,3]. It has been developed into a fixed-dose combination with piperaquine to treat uncomplicated P. falciparum malaria. Recently, novel triple combinations have been trialled, combining standard combinations with an additional partner drug to treat drug-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 and to assess and describe the relationship between antimalarial exposure and QT interval prolongation.
Methods: A total of 145 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 was administered, once daily for three days. 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. QT prolongation was modelled using a conservative linear direct-effect model.
Results: The pharmacokinetics of arterolane was described by a one-compartment disposition model with two-transit absorption compartments, piperaquine was described by a three-compartment disposition model with two-transit absorption compartments, and mefloquine was described by a two-compartment disposition model with two-transit absorption compartments while its active metabolite (carboxymefloquine) was best described by one disposition compartment. Co-administration of mefloquine did not significantly alter arterolane or piperaquine exposure Body weight was included as an allometric function on all clearance and volume parameters. No significant difference in QTc prolongation was observed between standard treatment with arterolane-piperaquine and the triple combination.
Conclusions: This study successfully characterised the population pharmacokinetic properties of arterolane, piperaquine and mefloquine in Kenyan children with uncomplicated malaria. No drug-drug interaction was found, and there was no increase in drug-associated QT prolongation in the triple combination therapy, supporting the safety of this novel triple combination regimen.
References:
- Organization, W.H., World Malaria Report 2024. 2024: World Health Organization.
- 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.
- 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