Bioavailability of protein therapeutics in rats following inhalation exposure: Relevance to occupational exposure limit calculations.

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.

The synthesis of a carbon-14 labeled pegylated Adnectin™ for placental transfer studies in guinea pigs.

Adnectins™ are novel fibronectin-based proteins containing domains engineered to bind to targets of therapeutic interest. The molecular weights of adnectins are less than conventional monoclonal antibodies but larger than traditional small molecules. Until now, there has been no information on the placental transfer of adnectins. To assess placental permeability to adnectins in pregnant guinea pigs, a radiolabeled adnectin, ATI-1072, bound to polyethylene glycol through a [(14) C]Maleimide linker, was synthesized from [1,4-(14) C]Maleic acid. This publication describes the synthesis and analysis of PEG-[(14) C]Maleimide-adnectin ([(14) C]ATI-1072).