The role of biopharmaceutics in the development of a clinical nanoparticle formulation of MK-0869: a Beagle dog model predicts improved bioavailability and diminished food effect on absorption in human
| Autor: | Karen C. Thompson, Alice E Loper, Linda Novak, Yunhui Wu, Cindy Chen, Gloria Y. Kwei, Lisa Hettrick, Kari Lynn, Storey David E, Udit Batra, Ray Higgins, Elizabeth Landis, Suhas D. Shelukar |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Absorption (pharmacology) Vomiting Chemistry Pharmaceutical Morpholines Drug Evaluation Preclinical Administration Oral Biological Availability Pharmaceutical Science Antineoplastic Agents Capsules Substance P Pharmacology Drug Administration Schedule Dosage form Absorption Food-Drug Interactions Upper Gastrointestinal Tract Clinical Trials Phase II as Topic Dogs Pharmacokinetics In vivo medicine Animals Humans Technology Pharmaceutical Aprepitant Active ingredient Clinical Trials Phase I as Topic Chemistry Biopharmaceutics Nausea Fasting Nanostructures Bioavailability Area Under Curve Models Animal Tablets medicine.drug |
| Zdroj: | International Journal of Pharmaceutics. 285:135-146 |
| ISSN: | 0378-5173 |
| DOI: | 10.1016/j.ijpharm.2004.08.001 |
| Popis: | MK-0869 (aprepitant), a potent substance P antagonist, is the active ingredient of EMEND which has recently been approved by the FDA for the prevention of chemotherapy-induced nausea and vomiting. Early clinical tablet formulations of MK-0869 showed significant food effects on absorption, suggesting that formulation could have a significant role in improving bioavailability. A Beagle dog model was developed in an effort to guide novel formulation development. Using the suspension of the micronized bulk drug used for the tablet formulations, the food effect on absorption was confirmed in the dog at a similar magnitude to that observed in humans. Further dog studies demonstrated a clear correlation between particle size and in vivo exposures, with the nanoparticle (NanoCrystal) colloidal dispersion formulation providing the highest exposure, suggesting dissolution-limited absorption. The NanoCrystal dispersion also eliminated the food effect on oral absorption in the dog at a dose of 2mg/kg. Regional absorption studies using triport dogs indicated that the absorption of MK-0869 was limited to the upper gastrointestinal tract. These results provided strong evidence that the large increase in surface areas of the drug nanoparticles could overcome the narrow absorption window and lead to rapid in vivo dissolution, fast absorption, and increased bioavailability. In addition, the dog model was used for optimizing formulation processes in which the nanoparticles were incorporated into solid dosage forms, and for selecting excipients to effectively re-disperse the nanoparticles from the dosage units. The human pharmacokinetic data using the nanoparticle formulation showed excellent correlations with those generated in the dog. |
| Databáze: | OpenAIRE |
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