Optimizing dihydroartemisinin-piperaquine dose regimens in a paediatric population: a pharmacokinetic-pharmacodynamic approach using monte-carlo simulations

Abstract

Objective: To evaluate and optimize the dose regimen of dihydroartemisinin-piperaquine in a paediatric population using Monte Carlo simulations. Methods: Different dosing regimens (i.e. the WHO recommended dose, manufacturers’ recommended dose, and a proposed increased dose) were investigated in 1,000 hypothetical paediatric patients. The pharmacokinetic model of piperaquine was assumed to follow a three-compartment distribution model with five transit-absorption compartments. The pharmacodynamic model was implemented as a time-toevent model with a constant hazard of malaria infections and a sigmoid Emax function for the protective effect of piperaquine. The pharmacokinetic and pharmacodynamic parameters were fixed according to previous modelling results and implemented in Berkley Madonna for simulations. Simulated day 7 piperaquine concentrations and the incidence of malaria infections during 2 months of follow-up were evaluated as pharmacokinetic and pharmacodynamic outcomes. Results: Low day 7 piperaquine plasma concentrations were observed in the paediatric population and were strongly correlated with a higher number of malaria infections when using a standard body weight-based dose regimen (18 mg piperaquine/kg). The standard three day regimen in the small children (5-10 kg weight) resulted in a two-month incidence of malaria of 30.7% when using the manufacturers’ dose recommendation as compared to 20.3% when using the proposed higher increased dose regimen. This is a 33.8% relative increase in piperaquine protective efficacy after the increased dose regimen. Additionally, a full 3-day regimen once a month for 3 consecutive months (i.e. seasonal intermittent preventive treatment) resulted in a 19.3% increased 5 months protective effect when using the proposed increased dose regimen as compared with the standard body weight-based dose in small children. Conclusion: In conclusion, the suggested increased piperaquine dose regimen in small children resulted in an increased protective efficacy after treatment (33.8%) and after seasonal intermittent preventive treatment (19.3%). Current piperaquine dose recommendations in small children should be urgently reviewed.