Malaria infections results in more than 400,000 deaths yearly, the majority being children under five years of age. Childhood malaria is also associated with long-term adverse developmental outcomes. Malaria is highly seasonal in some parts of Africa, peaking during the rainy season. Thus, malaria prevention in children is crucial in order to protect them from the disease and the complications associated with the disease. The World Health Organization (WHO) recommends insecticide-treated bed nets, indoor residual spraying and seasonal malaria chemoprevention (SMC) to prevent malaria. SMC consists of intermittent treatment with antimalarial drugs in order to eliminate and treat malaria infections before they cause any symptoms. The commonly used antimalarial drug combination of sulfadoxine-pyrimethamine is losing its effectiveness in certain regions in Africa due to resistance development. Dihydroartemisinin-piperaquine is an antimalarial drug combination therapy and a suitable alternative treatment option in SCM.
Small children, big problems
Children under five years of age are highly susceptible to malaria infection and to progress infections into severe disease, due to their relatively lower immunity, compared to adults. It is therefore crucial to protect these children from malaria infections. SMC provides such a protection but designing antimalarial dosing in young children is complicated, and it is not possible to simply scale adult dosing. Physiological functions that determine the elimination of drugs do not generally scale linearly with body weight. Thus, young children often need a relatively higher dosage compared to adults. Dosing young children with dosages scaled from adult regimens may lead to sub-therapeutic drug exposure, resulting in therapeutic failure and drug resistance development.
Our study aimed to answer; what is the appropriate dosing of SMC in young children?
Clinical trial design, mathematical modelling and simulations
We designed and conducted a clinical trial, giving dihydroartemisinin-piperaquine as SMC to young children in Burkina Faso during the rainy season. Blood samples were collected at different time points after drug administration and drug concentrations were measured to describe the drug exposure. Blood samples were also collected from kids to evaluate possible malaria infections by using microscopy. Mathematical and statistical modelling were conducted to characterise the pharmacological properties of piperaquine and its relationship to malaria prevention effects, i.e. the drug exposure-response relationships. Several sets of equations were developed and tested in order to describe the exposure-response relationship and to evaluate what patient-specific factors that had an impact on the pharmacological properties and malaria outcome. The final model showed a very high predictive performance and was consequently used to simulate several “what-if scenarios” in order to determine the optimal dosing of dihydroartemisinin-piperaquine when given as SMC.
Right doses, right time
The same body weight-adjusted dose (mg/kg) in young children resulted in a lower drug levels compared to adults. Results presented here supported the newly recommended higher dosage of dihydroartemisinin-piperaquine in young children. We also demonstrated a substantial reduction in malarial infections by extending the SMC for one additional month during the rainy season (to a total of 4 months of SMC). Increasing the dosage and the length of SMC (from 3 months to 4 months) resulted in a relative reduction of malaria of up to 58% during the rainy season in this region.
We believe that prompt malaria diagnostics, availability and low cost of effective antimalarial drugs, efficient malaria chemoprophylaxis, and efficient and resolute malaria elimination strategies can contribute to a malaria-free world.
The World Health Organization. Guidelines for the treatment of malaria, Second end. (WHO, Geneva, 2010)
The World Health Organization. Guidelines for the treatment of malaria, Third end. (WHO, Geneva, 2015)
Chotsiri P, Zongo I, Milligan P, Compaore YD, Somé FA, Chandramohan D, Hanpithakpong W, Nosten F, Greenwood B, Rosenthal PJ, White NJ, Ouédraogo J, & Tarning J. Optimal dosing of dihydroartemisinin-piperaquine for seasonal malaria chemoprevention in young children. Nature Communications 2019; 10: 480.
Tarning J, Zongo I, Somé FA, Rouamba N, Parikh S, Rosenthal PJ, Hanpithakpong W, Jongrak N, Day NP, White NJ, Nosten F, Ouedraogo JB, Lindegardh N. Population pharmacokinetics and pharmacodynamics of piperaquine in children with uncomplicated falciparum malaria. Clinical pharmacology and therapeutics 2012; 91: 497-505.
Authors: Palang Chotsiri & Joel Tarning