Abstract
After more than 40 years of use, Praziquantel (PZQ) still remains the drug of choice for the treatment of intestinal and urogenital schistosomiasis. Its anti-parasitic activity resides primarily in the (R)-enantiomer. Hitherto neither the molecular target nor the pharmacokinetic-pharmacodynamic relationship have been fully elucidated. Here we investigated the efficacy and pharmacokinetics of PZQ in the Schistosoma mansoni mouse model to determine the key factors that drive its efficacy. Dose-response studies with racemic PZQ with or without addition of an irreversible pan-cytochrome P450 (CYP) inhibitor, 1-aminobenzotriazole (ABT), were performed. In addition, efficacy of PZQ in the presence of the CYP inducer, dexamethasone (DEX), was determined. Plasma samples were obtained by tail vein bleeding at 4 time points. The (R)-PZQ levels were determined using a LC-MS/MS method. Non-compartmental pharmacokinetic analysis was performed using PKsolver. In addition, experiments using an enhanced in vitro assay were conducted. We found that the use of ABT increased (R)-PZQ plasma exposures in the systemic circulation by ~10 to 20 fold but the latter were not predictive of efficacy. The use of DEX decreased plasma exposures of (R)-PZQ in the systemic circulation by ~10 fold without reducing efficacy. We extrapolated the (R)-PZQ concentrations in mouse portal vein / mesenteric veins from the systemic exposures and found that a free exposure of (R)-PZQ of ~ 20 μM*h in the portal vein was needed to obtain a worm burden reduction >60%. It is suggested that the high (R)-PZQ concentrations available before the hepatic first pass metabolism drive the efficacy against S. mansoni adult worms residing in the mesenteric veins. It is then possible that the current dosing regimen of 40 mg/kg in preventive chemotherapy programs may provide suboptimal concentrations in low-weight patients such as children, due to smaller total amounts of drug administered, and may consequently result in lower cure rates.
Highlights
Schistosomiasis [1,2,3] causes significant morbidity and mortality in subtropical and tropical regions of the world and estimates show that at least 258 million people required preventive treatment for schistosomiasis in 2014 [4]
For adults infected with intestinal schistosomiasis, a single oral dose of PZQ at 40 mg/kg is generally recommended by the World Health Organisation for preventive chemotherapy programs
By reducing hepatic metabolism with a pan-cytochrome P450 (CYP) inhibitor, we studied the systemic plasma exposure relationship versus activity in the Schistosoma mansoni mouse model
Summary
Schistosomiasis [1,2,3] causes significant morbidity and mortality in subtropical and tropical regions of the world and estimates show that at least 258 million people required preventive treatment for schistosomiasis in 2014 [4]. After more than 40 years of use, neither the molecular target nor the pharmacokinetic-pharmacodynamic (PK/PD) relationship have been elucidated [9,10]. These lacking data hamper progression of much needed new chemical entities and may raise questions regarding the suboptimal response of PZQ observed in some published pediatric studies [11,12]. To investigate the efficacy and pharmacokinetics of PZQ in a preclinical setting, the well-established Schistosoma mansoni mouse model is probably the most suited as it uses the most predominant species infecting humans with intestinal schistosomiasis and resides in the same target organ, i.e. the mesenteric veins [13]. To enhance the understanding of the PK/PD relationship, an opposite strategy can be applied, by pre-treating the mice with dexamethasone (DEX), an inducer of several CYPs, before PZQ
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