Assessing the risk of drug crystallization in vivo
| Autor: | Yang Wu, Dieter M. Drexler, Joseph B. Santella, Thomas Brodie, Janet DiPiero, Stefan Ruepp, Umesh Hanumegowda, Brian Gemzik, Ching-Chiang Su, Evan B. Janovitz, Randy White, Michael J. Hageman, Julie Carman, John Hynes, Duohai Pan, John R. Megill |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Risk Drug Duodenum Pyridines media_common.quotation_subject Primary Cell Culture Biological Availability Spectrum Analysis Raman Toxicology law.invention Rats Sprague-Dawley In vivo law Drug Discovery Macrophages Alveolar Microscopy Animals Crystallization media_common Pharmacology Polarized light microscopy Chemistry Rats Bioavailability Interleukin-1 Receptor-Associated Kinases Solubility Drug development Tolerability Pyrazoles Female Biomedical engineering |
| Zdroj: | Journal of Pharmacological and Toxicological Methods. 96:1-8 |
| ISSN: | 1056-8719 |
| DOI: | 10.1016/j.vascn.2018.12.003 |
| Popis: | Introduction Low intrinsic solubility leading to poor oral bioavailability is a common challenge in drug discovery that can often be overcome by formulation strategies, however, it remains a potential limitation that can pose challenges for early risk assessment and represent a significant obstacle to drug development. We identified a selective inhibitor (BMS-986126) of the IL-1 receptor–associated kinase 4 (IRAK4) with favorable properties as a lead candidate, but with unusually low intrinsic solubility of Methods Conventional histopathology identified the issue of crystal formation in vivo. Subsequent investigative work included confocal Raman micro-spectroscopy, MALDI-MS, polarized light microscopy of fresh wet-mount tissue scrapings and transmission electron microscopy. Results BMS-986126 was advanced into a 2-week toxicology study in rats. The main finding in this study was minimal granulomatous inflammation in the duodenum, associated with the presence of birefringent crystals at the highest dosage of 100 mg/kg/day. Considering the safety margin, and the single location of the lesion, BMS-986126 was further progressed into IND-enabling toxicology studies where tolerability deteriorated with increasing dosing duration. Birefringent crystals and granulomatous inflammation were detected in multiple organs at dosages ≥20 mg/kg/day. Raman spectroscopy confirmed the identity of the crystals as BMS-986126. Therefore, follow up investigations were conducted to further characterize drug crystallization and to evaluate detection methods for their potential to reliably detect in vivo crystallization early. Discussion The purpose of our efforts was to identify critical factors influencing in vivo drug crystallization and to provide a preliminary assessment (based on one compound) which method would be best suited for identifying crystals. Results indicated a combination of methods was required to provide a complete assessment of drug crystallization and that a simple technique, scraping of freshly collected tissue followed by evaluation under polarizing light was suitable for detecting crystals. However, dosing for 2 weeks was required for crystals to grow to a clearly detectable size. |
| Databáze: | OpenAIRE |
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