Optimizing dihydroartemisinin-piperaquine dose regimens in a paediatric population: a pharmacokinetic-pharmacodynamic approach using monte-carlo simulations
Issued Date
2013
Resource Type
Language
eng
Rights
Mahidol University
Suggested Citation
Palang Chotsiri, พลัง โชติศิริ, Tarning, Joel (2013). Optimizing dihydroartemisinin-piperaquine dose regimens in a paediatric population: a pharmacokinetic-pharmacodynamic approach using monte-carlo simulations. Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/63362
Title
Optimizing dihydroartemisinin-piperaquine dose regimens in a paediatric population: a pharmacokinetic-pharmacodynamic approach using monte-carlo simulations
Author(s)
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.
Description
Joint International Tropical Medicine Meeting 2013: Towards global health: an Asian paradigm of Tropical Medicine 11-13 December 2013
Centara Grand Bangkok Convention Center at Central World, Bangkok, Thailand. Bangkok: Faculty of Tropical Medicine, Mahidol University; 2013. p.171.