Preclinical and pharmacokinetic studies of praziquantel, the cornerstone of schistosomiasis treatment

Schistosomiasis remains the most important helminthic disease, infecting over 240 millions of people in tropical and subtropical areas of the world, while close to 800 millions of people live at risk of contracting it. Unfortunately, children are among the most affected and the disease often results in stunting, malnutrition and cognitive and physical retardation. Praziquantel (PZQ), being effective, cheap and safe, remains the cornerstone of schistosomiasis treatment and is distributed on a wide scale within drug administration programs. Until recently it was believed schistosomiasis among young children, below the age of six years, is not very common and consequently, they were not regularly treated. However, in 2011 WHO acknowledged these children are a risk group and could be included in the administration programs in the future, but pharmacokinetic data (PK), crucial to establish effective and safe dose of PZQ for pre-schoolers, is not readily available. Furthermore, in vitro and in vivo data on antischistosomal activity of PZQ for S. haematobium, responsible for the highest number of infections, is lacking. Moreover, PK studies in this sensitive population are tedious in conduct and call for a more patient friendly sampling approach, while the quality of sampling remains uncompromised.
The aim of the present thesis was to gain more information about activity of both enantiomers of PZQ, R- and SPZQ, as well as the racemic drug and the main human metabolite (R-trans-4-hydroxy-PZQ) in vitro, in vivo and in humans.
S. haematobium was studied in vitro and in vivo to evaluate and confirm its greater susceptibility to PZQ, compared to S. mansoni and S. japonicum. This species of schistosomes is characterised with a life-cycle, tedious to maintain in laboratory conditions and consequently, understudied compared to other species of the parasites. We determined IC50 values for racemic PZQ, both enantiomers and the main human metabolite on adult worms in vitro. Moreover, ED50 values for both enantiomers and the racemic drugs in hamster model were reported in vivo. In light of the development of paediatric formulation for PZQ, it would be important to evaluate how these findings translate to humans.
Two PK studies were conducted within dose finding studies to investigate PK of both PZQ enantiomers and the main human metabolite. For the first time, PK parameters, such as area under the curve, maximal blood concentration and half-life of these analytes were revealed and compared. Influences, e.g. age and infection species on the PK processes were investigated. Moreover, a PK model for in depth study of influence on metabolic processes of RPZQ is currently under development.
As a sub-study within SAC infected with S. haematobium, a novel micro-sampling device, called Mitra™, was evaluated in comparison to established dried blood spots technique, in the laboratory and under field conditions. A sample preparation method for PZQ with Mitra™ was established, optimised and validated in compliance with Food and Drug Administration guidelines. Owing to practicality and simplicity during both sampling and extraction process, Mitra™ showed great potential; however, overestimation of concentrations compared to dried blood spots in incurred, but not in spiked samples, is yet to be clarified.
To conclude, we revealed PK parameters of the main entities, contributing to antischistosomal activity of PZQ. The PK model for RPZQ will reveal influences on metabolic processes of the proposed eutomer of PZQ. These findings will contribute to establishment and tailoring of guidelines for treating paediatric populations, infected with schistosomiasis, using PZQ. Validation of Mitra™ as a potential micro-sampling tool for PK studies will pave the way towards higher quality of sampling while maintaining high patient adherence. Last but not least, the study of S. haematobium in vitro and in vivo will compliment the existing data on activity of PZQ towards different species of schistosomes. Since SPZQ and the main human metabolite showed non-negligible activity towards S. haematobium, the decision whether to develop an enantio-pure paediatric formulation, consisting of RPZQ only, should be carefully evaluated.