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Activity and pharmacokinetics of a praziquantel crystalline polymorph in the Schistosoma mansoni mouse model.
Journal article

Activity and pharmacokinetics of a praziquantel crystalline polymorph in the Schistosoma mansoni mouse model.

  • Lombardo FC Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002 Basel, Switzerland; Universität Basel, Petersplatz 1, CH-4001 Basel, Switzerland.
  • Perissutti B Department of Chemical and Pharmaceutical Sciences, University of Trieste, p.le Europa 1, 34127 Trieste, Italy.
  • Keiser J Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002 Basel, Switzerland; Universität Basel, Petersplatz 1, CH-4001 Basel, Switzerland. Electronic address: jennifer.keiser@swisstph.ch.
  • 2019-07-03
Published in:
  • European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V. - 2019
Activity
Pharmacokinetics
Polymorph B
Praziquantel
Schistosoma mansoni
Animals
Anthelmintics
Biological Availability
Crystallization
Disease Models, Animal
Female
Mice
Praziquantel
Schistosoma mansoni
Schistosomiasis mansoni
Solubility
English Schistosomiasis is a global disease of significant public health relevance. Only one racemic drug, praziquantel, characterized by low bioavailability, low water solubility and extensive first pass metabolism, is currently available. We studied a new praziquantel formulation (polymorph B), which is based on a racemic praziquantel crystalline polymorph (TELCEU01). Its in vitro activity was tested on newly transformed schistosomula (NTS) and adult Schistosoma mansoni. In vivo studies were conducted in mice harboring chronic S. mansoni infections. Pharmacokinetic (PK) profiles of R- and S-praziquantel and R- and S- polymorph B following oral administration with both formulations were generated by sampling mice at 30, 60, 240 min and 24 h post-treatment, followed by LC-MS/MS analysis. PK parameters were calculated using a non-compartmental analysis with a linear trapezoidal model. In vitro, commercial praziquantel and the polymorph B performed similarly on both NTS (IC50 = 2.58 and 2.40 µg/mL at 72 h) and adults (IC50 = 0.05 and 0.07 µg/mL at 72 h). Praziquantel showed higher in vivo efficacy with an ED50 of 58.75 mg/kg compared to an ED50 of 122.61 mg/kg for the polymorph B. The PK profiles of the two drugs exhibited differences: R-praziquantel showed an overall 40% higher area under the plasma drug concentration-time curve (AUC0→24) (R-praziquantel = 3.42; R-polymorph B = 2.05 h*µg/mL) and an overall 30% lower apparent clearance (Cl/F) (R-praziquantel = 70.68 and R-polymorph B = 97.63 (mg)/(µg/mL)/h). Despite the lack of improved activity and PK properties of polymorph B against S. mansoni, here presented; research on pharmaceutical polymorphism remains a valid and cost-effective option for the development of new praziquantel formulations with enhanced properties such as increased solubility and/or dissolution.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/232512
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