Introduction: Antimalarial drug resistance threatens the efficacy of artemisinin combination therapies (ACTs), the first-line treatment for Plasmodium falciparum malaria. Standard ACTs combine a fast-acting artemisinin derivative with a single long-acting partner drug, whereas novel triple artemisinin combination therapies (TACTs) co-administer two long-acting partner drugs. Recent clinical trials of TACTs demonstrate favourable tolerability and high efficacy against both artemisinin-resistant and wildtype parasite strains. This study aimed to estimate the pharmacodynamic properties of the TACT artemether-lumefantrine plus amodiaquine (AL-AQ) in settings of artemisinin resistance.
Methods: A mechanistic pharmacodynamic (PD) model of malaria infection was fit to data from the TACT-CV clinical trial (Peto et al., 2022), which compared AL-placebo to AL-AQ for the treatment of uncomplicated P. falciparum malaria. Pharmacokinetic (PK) profiles for each drug, alongside genotype data (classifying infections as artemisinin-resistant or wildtype), were used to fit the discrete-time PD model to the parasitaemia measurement data.
Results: The dataset included 310 adults from Vietnam (n=51) and Cambodia (n=259), with 154 patients administered AL-placebo and 156 AL-AQ. A subset of Vietnamese patients (n=38, 20 AL-Placebo and 18 AL-AQ) had dense sampling for measurement of drug concentrations, while the remaining patients were sampled at approximately 1 and 168 hours post treatment initiation.
We generated per-patient hourly drug-concentration values for 42 days post-treatment initiation, by combining patient weights, doses and dose times with published PK models of the TACT-CV data (Ding et al., 2026). Of 305 successfully genotyped infections, 174 (including 36 of 38 from the rich PK sampling group) were classified as artemisinin resistant. There were 13 PCR-confirmed treatment failures documented within 42 days of follow-up, with 8 in the AL-placebo arm and 12 classified as artemisinin-resistant.
The PD model was fit and converged appropriately within a Bayesian framework, implemented in STAN. Posterior predictive checks confirmed the parasitaemia data (including post-treatment failures) were well captured by the model. Preliminary results estimate the artemisinin-resistant infections have Emax and EC50 values for artemether/dihydroartemisinin adjusted by factors of 0.29 (95% credible interval: [0.14, 0.56]) and 1.59 (95% CI: [1.18, 1.90]) respectively, when compared to wildtype infections.
Conclusion: The posterior parameter distributions obtained through this modelling facilitate in silico evaluation of AL-AQ treatment outcomes and can guide dose optimisation under potential future artemisinin drug resistance scenarios in Africa. This PK-PD modelling framework can be readily adapted to other P. falciparum antimalarial treatments, comparing treatment efficacy of novel TACTs and standard ACTs through simulation.
Funding: Bill & Melinda Gates Foundation, Wellcome Trust.
References:
- Ding, J., Hoglund, R. M., van der Pluijm, R. W., Callery, J. J., Peto, T. J., Tripura, R., Das, S., Chau, N. H., Promnarate, C., Mukaka, M., Dysoley, L., Fanello, C., Onyamboko, M. A., Anvikar, A. R., Mayxay, M., Smithuis, F., von Seidlein, L., Dhorda, M., Amaratunga, C., . . . Tarning, J. (2026). Population pharmacokinetics of artemether-lumefantrine plus amodiaquine in patients with uncomplicated Plasmodium falciparum malaria. Br J Clin Pharmacol, 92(2), 589-605. https://doi.org/10.1002/bcp.70301
- Peto, T. J., Tripura, R., Callery, J. J., Lek, D., Nghia, H. D. T., Nguon, C., Thuong, N. T. H., van der Pluijm, R. W., Dung, N. T. P., Sokha, M., Van Luong, V., Long, L. T., Sovann, Y., Duanguppama, J., Waithira, N., Hoglund, R. M., Chotsiri, P., Chau, N. H., Ruecker, A., . . . Dondorp, A. M. (2022). Triple therapy with artemether-lumefantrine plus amodiaquine versus artemether-lumefantrine alone for artemisinin-resistant, uncomplicated falciparum malaria: an open-label, randomised, multicentre trial. Lancet Infect Dis, 22(6), 867-878. https://doi.org/10.1016/S1473-3099(21)00692-7