Population pharmacokinetics and pharmacodynamics of praziquantel in Ugandan children with intestinal schistosomiasis: higher dosages are required for maximal efficacy

Bustinduy, A. L. et al. (2016) Population pharmacokinetics and pharmacodynamics of praziquantel in Ugandan children with intestinal schistosomiasis: higher dosages are required for maximal efficacy. mBio, 7(4), e00227-16. (doi: 10.1128/mBio.00227-16) (PMID:27507822) (PMCID:PMC4992966)

Abstract

Each year, millions of African children receive praziquantel (PZQ) by mass drug administration (MDA) to treat schistosomiasis at a standard single dose of 40 mg/kg of body weight, a direct extrapolation from studies of adults. A higher dose of 60 mg/kg is also acceptable for refractory cases. We conducted the first PZQ pharmacokinetic (PK) and pharmacodynamic (PD) study in young children comparing dosing. Sixty Ugandan children aged 3 to 8 years old with egg patent Schistosoma mansoni received PZQ at either 40 mg/kg or 60 mg/kg. PK parameters of PZQ racemate and enantiomers (R and S) were quantified. PD outcomes were assessed by standard fecal egg counts and novel schistosome-specific serum (circulating anodic antigen [CAA]) and urine (circulating cathodic antigen [CCA]) antigen assays. Population PK and PD analyses were performed to estimate drug exposure in individual children, and the relationship between drug exposure and parasitological cure was estimated using logistic regression. Monte Carlo simulations were performed to identify better, future dosing regimens. There was marked PK variability between children, but the area under the concentration-time curve (AUC) of PZQ was strongly predictive of the parasitological cure rate (CR). Although no child achieved antigenic cure, which is suggestive of an important residual adult worm burden, higher AUC was associated with greater CAA antigenic decline at 24 days. To optimize the performance of PZQ, analysis of our simulations suggest that higher doses (>60 mg/kg) are needed, particularly in smaller children.

• Item Type: Articles
• Additional Information: This work was funded by Wellcome Trust grant UK 085440/Z/08/Z.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Scott, Dr Janet
• Authors: Bustinduy, A. L., Waterhouse, D., de Sousa-Figueiredo, J. C., Roberts, S. A., Atuhaire, A., Van Dam, G. J., Corstjens, P. L. A. M., Scott, J. T., Stanton, M. C., Kabatereine, N. B., Ward, S., Hope, W. W., and Stothard, J. R.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: mBio
• Publisher: American Society for Microbiology
• ISSN: 2150-7511
• ISSN (Online): 2150-7511
• Published Online: 09 August 2016
• Copyright Holders: Copyright © 2016 Bustinduly et al.
• First Published: First published in mBio 7(4): e00227-16
• Publisher Policy: Reproduced under a Creative Commons License