ToxSci Advance Access originally published online on August 19, 2009
Toxicological Sciences 2009 112(1):196-210; doi:10.1093/toxsci/kfp195
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Investigations of the Use of Bioavailability Data to Adjust Occupational Exposure Limits for Active Pharmaceutical Ingredients
* Merck & Co., Inc., Whitehouse Station, New Jersey 08889-0200
Schering-Plough Corp., Kenilworth, New Jersey 07033
Novartis, East Hanover, New Jersey 07936
IIT Research Institute, Chicago, Illinois 60616
¶ MedImmune, Gaithersburg, Maryland 20878
|| EV Sargent LLC, Clearwater, Florida 33767
1 To whom correspondence should be addressed at Merck & Co., Inc., Two Merck Drive, WS2W-18, Whitehouse Station, NJ 08889-0200. Fax (908) 735-1496. E-mail: bruce_naumann{at}merck.com
Received April 7, 2009; accepted August 10, 2009
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Abstract |
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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 D4 receptor antagonist, was compared following iv, po, intranasal (in), or intratracheal (it) administration. The relative bioavailability of MK-0679 was iv 
it > po 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/m3 for MK-0679 with particle sizes of 10 and 50 µm, 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.
Key Words: absorption; bioavailability; OEL; pharmaceutical; respiratory tract.