Juvenile animal testing of hydroxypropyl-β-cyclodextrin in support of pediatric drug development
| Autor: | Dirk Mariën, Luc De Schaepdrijver, Marieke Voets, Lieve Lammens, Marjolein van Heerden, Cheyma Rhimi |
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| Rok vydání: | 2015 |
| Předmět: |
Metabolic Clearance Rate
Administration Oral Pharmacology Kidney Toxicology Risk Assessment Excipients Rats Sprague-Dawley Species Specificity In vivo Oral administration Toxicity Tests Animals Humans Toxicokinetics Medicine Juvenile Juvenile animal business.industry beta-Cyclodextrins Age Factors Infant Newborn Infant 2-Hydroxypropyl-beta-cyclodextrin Renal Elimination medicine.anatomical_structure Renal physiology Injections Intravenous Models Animal Toxicity business |
| Zdroj: | Reproductive Toxicology. 56:87-96 |
| ISSN: | 0890-6238 |
| Popis: | Hydroxypropyl-β-cyclodextrin (HP-β-CD) is being explored as excipient for administration of poorly soluble NCE's in pediatrics. In support of pharmaceutical development, non-clinical studies were performed to investigate whether oral and intravenous administration of HP-β-CD showed a different response in juvenile rats versus adult rats. Juvenile rats received HP-β-CD via the intravenous route at dose levels of 50, 200 and 400mg/kg/day from postnatal day 16 to 44, or via oral gavage at 500, 1000 and 2000mg/kg/day from postnatal day 4 to 46. In addition to in vivo parameters, toxicokinetics and post-mortem evaluations were conducted. The main findings were related to the renal excretion of intact HP-β-CD and were regarded as non-adverse transient adaptive responses. The pathogenesis of the osmotic nephrosis-like changes are discussed. With increasing age a more effective renal clearance of HP-β-CD is present in line with the postnatal functional maturation of the kidney. In addition, following oral administration an increase in soft stools was seen which was related to osmotic water retention in the large intestine. The findings in the juvenile studies are very similar to those observed in previously performed adult rat studies at similar dose levels, same routes and similar or longer dose duration. No novel toxicity was seen in the juvenile studies. |
| Databáze: | OpenAIRE |
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