title: Investigations of the use of bioavailability data to adjust occupational exposure limits for active pharmaceutical ingredients.
abstract: Occupational exposure limits (OELs) for active pharmaceutical ingredients have traditionally been established using no-observed-adverse-effect levels derived from clinical studies employing po and iv routes of administration and by applying default uncertainty factors or chemical-specific adjustment factors. However, exposure by the inhalation or dermal route is more relevant in terms of occupational safety. In this investigation, to explore new methods for route-to-route extrapolation, the bioavailability of MK-0679, a leukotriene D(4) receptor antagonist, was compared following iv, po, intranasal (in), or intratracheal (it) administration. The relative bioavailability of MK-0679 was iv congruent with it > po congruent with in. Bioavailability correction factors (BCFs) of 2.0 and 0.6 were derived from these data to adjust a hypothetical OEL of 0.1 mg/m(3) for MK-0679 with particle sizes of 10 and 50 mum, respectively. These BCFs were used to adjust the OEL established using po clinical data, to reflect the differences in bioavailability following deposition in different regions of the respiratory tract. To further investigate how bioavailability data could be used in setting OELs, a preliminary pharmacokinetic (PK) model was developed to describe the time course of plasma concentrations using the data from the route comparison study. An inhalation study was then performed to test the validity of using either empirical data or modeling approaches to derive BCFs when setting OELs. These investigations demonstrated how the use of route-specific PK data could reduce some of the uncertainties associated with route-to-route extrapolation and allow for improved precision and quantitative adjustments when establishing OELs. Further investigations are needed to better understand the factors responsible for differences in systemic uptake following deposition in different regions of the respiratory tract and how these can be generalized across different classes of soluble compounds.
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey 08889-0200, USA. bruce_naumann@merck.com
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Naumann
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Weideman
authors.forename: Ramesh
authors.initials: R
authors.lastname: Sarangapani
authors.forename: Shu-Cheih
authors.initials: SC
authors.lastname: Hu
authors.forename: Rakesh
authors.initials: R
authors.lastname: Dixit
authors.forename: Edward V
authors.initials: EV
authors.lastname: Sargent
mesh_terms: D000818:Animals; D001682:Biological Availability; D020024:Leukotriene Antagonists / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D016273:Occupational Exposure; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011422:Propionates / Q000097:blood / Q000493:pharmacokinetics*; D011804:Quinolines / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020024:Leukotriene Antagonists; D004364:Pharmaceutical Preparations; D011422:Propionates; D011804:Quinolines; C059141:verlukast