LAUSR

ABSTRACT 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 (10–150kDa), 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>4.5h 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. HIGHLIGHTSFor typical large proteins (10–150kDa), systemic bioavailability in the rat following inhalation is low, at ˜≤1%.Addition of a PEG moiety on a protein can considerably decrease systemic bioavailability.Direct effects on the lung should be considered when assessing the hazard potential for proteins that have lung targets.The application of a default PK factor adjusting for 1% bioavailability is warranted when calculating OELs.