Evaluation of the pharmacokinetic-pharmacodynamic relationship of praziquantel in the Schistosoma mansoni mouse model.
| Title: | Evaluation of the pharmacokinetic-pharmacodynamic relationship of praziquantel in the Schistosoma mansoni mouse model. |
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| Authors: | Nada Abla, Jennifer Keiser, Mireille Vargas, Natalie Reimers, Helmut Haas, Thomas Spangenberg |
| Source: | PLoS Neglected Tropical Diseases, Vol 11, Iss 9, p e0005942 (2017) |
| Publisher Information: | Public Library of Science (PLoS), 2017. |
| Publication Year: | 2017 |
| Collection: | LCC:Arctic medicine. Tropical medicine LCC:Public aspects of medicine |
| Subject Terms: | Arctic medicine. Tropical medicine, RC955-962, Public aspects of medicine, RA1-1270 |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 1935-2727 1935-2735 |
| Relation: | http://europepmc.org/articles/PMC5626502?pdf=render; https://doaj.org/toc/1935-2727; https://doaj.org/toc/1935-2735 |
| DOI: | 10.1371/journal.pntd.0005942 |
| Access URL: | https://doaj.org/article/2773722746664e0cb48de9988ceb99b5 |
| Accession Number: | edsdoj.2773722746664e0cb48de9988ceb99b5 |
| Database: | Directory of Open Access Journals |
| ISSN: | 19352727 19352735 |
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| DOI: | 10.1371/journal.pntd.0005942 |
| Published in: | PLoS Neglected Tropical Diseases |
| Language: | English |