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Within-host malaria modelling to improve the treatment of malaria

Artemisinin-based combination therapies are the first line treatment for falciparum malaria and are administered to >200 million people annually. However artemisinin resistant parasites have spread across Southeast Asia, and have now emerged in Africa and Papua New Guinea. Mathematical models integrating blood antimalarial drug concentrations with the parasite-time profile of an infected individual provide an avenue to studying drug action. We have developed biologically informed within-host mathematical models for exploring treatment outcomes following artemisinin-based combination therapies (ACTs). Control and elimination of vivax malaria presents specific challenges because the parasite forms dormant liver stages (hypnozoites) that can reactivate to cause relapses of malaria, weeks or months later. The only available drugs for clearing hypnozoites are primaquine and tafenoquine, both of which can cause life-threatening haemolysis in people with glucose-6-phospate dehydrogenase (G6PD) deficiency. G6PD deficiency is one of the most common enzymopathies in malaria-endemic regions, with prevalence ranging from 3% to 35%. We have developed a mathematical model that simulates the production and destruction of red cells to assess the safety of primaquine dosing regimens. We apply state of the art Bayesian methods to validate the within-host models against data from controlled human malaria infection studies and multinational clinical trials.

Tully MK, Commons RJ, Simpson JA, Price DJ: Quantification of cure for pharmacodynamic models of antimalarial drugs: Deterministic versus stochastic approaches. Br J Clin Pharmacol 2026, 92:317-322.

Moss R, Dini S, Kho S, Barber BE, Buffet PA, Rajasekhar M, Price DJ, Anstey NM, Simpson JA: The role of the spleen in red blood cell loss caused by malaria: A mathematical model. PLoS Comput Biol 2026, 22:e1013865.

Tully MK, Dini S, Flegg JA, McCarthy JS, Price DJ, Simpson JA: Evaluation of a Bayesian hierarchical pharmacokinetic-pharmacodynamic model for predicting parasitological outcomes in Phase 2 studies of new antimalarial drugs. Antimicrob Agents Chemother 2024, 68:e0086324.

Cao P, Kho S, Grigg MJ, Barber BE, Piera KA, William T, Poespoprodjo JR, Jang IK, Simpson JA, McCaw JM, Anstey NM, McCarthy JS, Britton S: Characterisation of Plasmodium vivax lactate dehydrogenase dynamics in P. vivax infections. Commun Biol 2024, 7:355.

Saralamba S, Simpson JA, Choosri N, White L, Pan-Ngum W, Dondorp AM, White NJ: An artesunate pharmacometric model to explain therapeutic responses in falciparum malaria. J Antimicrob Chemother 2023.

Haghiri A, Price DJ, Fitzpatrick P, Dini S, Rajasekhar M, Fanello C, Tarning J, Watson J, White NJ, Simpson JA: Evidence based optimal dosing of intravenous artesunate in children with severe falciparum malaria. Clin Pharmacol Ther 2023.

Zaloumis SG, Whyte JM, Tarning J, Krishna S, McCaw JM, Cao P, White MT, Dini S, Fowkes FJI, Maude RJ, Kremsner P, Dondorp A, Price RN, White NJ, Simpson JA: Development and Validation of an In Silico Decision Tool To Guide Optimization of Intravenous Artesunate Dosing Regimens for Severe Falciparum Malaria Patients. Antimicrob Agents Chemother 2021, 65.

Dini S, Zaloumis SG, Price DJ, Gobeau N, Kummel A, Cherkaoui M, Moehrle JJ, McCarthy JS, Simpson JA: Seeking an optimal dosing regimen for OZ439/DSM265 combination therapy for treating uncomplicated falciparum malaria. J Antimicrob Chemother 2021.

Cao P, Collins KA, Zaloumis S, Wattanakul T, Tarning J, Simpson JA, McCarthy J, McCaw JM: Modeling the dynamics of Plasmodium falciparum gametocytes in humans during malaria infection. Elife 2019, 8:e49058.

Zaloumis SG, Cao P, Dini S, Davenport MP, Cromer D, Khoury DS, Fowkes FJI, McCaw JM, Simpson JA: In silico investigation of the decline in clinical efficacy of artemisinin combination therapies due to increasing artemisinin and partner drug resistance. Antimicrob Agents Chemother 2018, 62.

Dini S, Zaloumis S, Cao P, Price RN, Fowkes FJI, van der Pluijm RW, McCaw JM, Simpson JA: Investigating the efficacy of triple artemisinin-based combination therapies (TACTs) for treating Plasmodium falciparum malaria patients using mathematical modelling. Antimicrob Agents Chemother 2018, 62:e01068-01018.