Background
Amodiaquine-containing antimalarial combinations are effective for seasonal malaria chemoprevention (SMC) in children under five in high-burden regions like Nigeria1. The antimalarial activity of amodiaquine is dependent on the concentration of Desethylamodiaquine2. However, the efficacy of SMC can be influenced by suboptimal drug and metabolite exposure, as well as variations in dosing regimens, which underscores the need for pharmacokinetic research to optimise its implementation, highlighting the need for population-specific studies. The objective of this study was to develop a population pharmacokinetic (PopPK) model for amodiaquine to inform its use in SMC interventions in Nigeria.
Methods
A PopPK model using 266 plasma concentrations of amodiaquine pooled from 34 healthy Nigerian volunteers across two pharmacokinetic studies3,4 was developed for amodiaquine via Monolix 2023R1 software. Nonparametric bootstrap analysis and model-based simulations for day 3, day 7, and day 28 and maximum concentrations of desethylamodiaquine were implemented in R package.
Results
A two-compartment model with two transit compartments best described the pharmacokinetics of amodiaquine, with a clearance of 2200 L/hr and a mean transit time of 0.896 h. The allometric scaling of weight on all clearance and volume distribution parameters significantly improved the model. Simulations demonstrated that DEAQ concentrations on day 7 were higher than the established efficacy thresholds from studies outside Nigeria (e.g., mean day 7 concentrations of 138.27 ng/ml in adults and 104.96 ng/ml in paediatrics). This indicates the suitability of the current dosing regimen for SMC in Nigeria.
Conclusion
The study highlights that amodiaquine’s current dosing is suitable for achieving the sustained therapeutic concentrations necessary for effective SMC in Nigeria. The findings also emphasize the need for further research in malaria patients to assess the influence of parasitaemia, co-administered drugs, and genetic polymorphisms, which may contribute to the observed interindividual variability in pharmacokinetic profiles.
References
- World Health Organization. Seasonal malaria chemoprevention. World Health Organization. Published online 2013:1-56. https://www.who.int/malaria/areas/preventive_therapies/children/en/
- Parikh S, Ouedraogo JB, Goldstein JA, Rosenthal PJ, Kroetz DL. Amodiaquine metabolism is impaired by common polymorphisms in CYP2C8: Implications for malaria treatment in Africa. Clin Pharmacol Ther. 2007;82(2):197-203. doi:10.1038/sj.clpt.6100122
- Olawoye OS, Adeagbo BA, Bolaji OO. Moringa oleifera leaf powder alters the pharmacokinetics of amodiaquine in healthy human volunteers. J Clin Pharm Ther. 2018;43(5):626-632. doi:10.1111/jcpt.12725
- Ademisoye AA, Soyinka JO, Olawoye SO, et al. Induction of Amodiaquine Metabolism by Rifampicin Following Concurrent Administration in Healthy Volunteers. J Explor Res Pharmacol. 2018;3(3):71-77. doi:10.14218/jerp.2017.00024
