Bioavailability of protein therapeutics in rats following inhalation exposure: Relevance to occupational exposure limit calculations
Autor: | Hui Wei, Neil Mathias, Jessica C. Graham, Aaron P. Yamniuk, Bonnie Wang, Irvith M. Carvajal, Julien Susan D, Janet Gould, Helen G. Haggerty, Michael J. Graziano, Jedd Hillegass, Alex Kozhich, Todd Davidson |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Drug Male media_common.quotation_subject Biological Availability Receptors Fc Pharmacology Toxicology 030226 pharmacology & pharmacy Polyethylene Glycols Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Administration Inhalation Medicine Animals Occupational exposure limit Lung media_common Inhalation exposure medicine.diagnostic_test Inhalation L-Lactate Dehydrogenase business.industry Proteins General Medicine Bioavailability 030104 developmental biology Bronchoalveolar lavage medicine.anatomical_structure Maximum Allowable Concentration business Bronchoalveolar Lavage Fluid |
Zdroj: | Regulatory toxicology and pharmacology : RTP. 100 |
ISSN: | 1096-0295 |
Popis: | Protein therapeutics represent a rapidly growing proportion of new medicines being developed by the pharmaceutical industry. As with any new drug, an Occupational Exposure Limit (OEL) should be developed to ensure worker safety. Part of the OEL determination addresses bioavailability (BA) after inhalation, which is poorly understood for protein therapeutics. To explore this, male Sprague-Dawley rats were exposed intravenously or by nose-only inhalation to one of five test proteins of varying molecular size (10–150 kDa), including a polyethylene glycol-conjugated protein. Blood, lung tissue and bronchoalveolar lavage (BAL) fluid were collected over various time-points depending on the expected test protein clearance (8 minutes-56 days), and analyzed to determine the pharmacokinetic profiles. Since the BAL half-life of the test proteins was observed to be > 4.5 h after an inhalation exposure, accumulation and direct lung effects should be considered in the hazard assessment for protein therapeutics with lung-specific targets. The key finding was the low systemic bioavailability after inhalation exposure for all test proteins (∼≤1%) which did not appear molecular weight-dependent. Given that this study examined the inhalation of typical protein therapeutics in a manner mimicking worker exposure, a default 1% BA assumption is reasonable to utilize when calculating OELs for protein therapeutics. |
Databáze: | OpenAIRE |
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