Verlukast

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.

Asthma is a chronic inflammatory disease that is associated with widespread but variable airflow obstruction. The mechanisms that lead to airflow obstruction in asthma are bronchoconstriction, mucosal edema, increased secretion of mucus, and an inflammatory-cell infiltrate that is rich in eosinophils. Leukotrienes (LTs) B4, C4, D4, and E4 have been shown experimentally to play a role in each of these inflammatory mechanisms and to mimic the pathologic changes seen in asthma. Inhaled LTC4 and LTD4 are the most potent bronchoconstrictors yet studied in human subjects. LTC4 and LTD4 also may cause migration of inflammatory cells into the asthmatic airway. LTs are derived from the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism, and increased production of LTs has been demonstrated in patients who have asthma. Leukotriene receptor antagonists and specific inhibitors of the 5-LO pathway hold great promise as new therapies to treat asthma. Because LTC4, LTD4, and LTE4 appear to interact with a common LTD4 receptor, selective LTD4 receptor antagonists (eg, pranlukast [SB205312/ONO-1078], zafirlukast [ICI 204,219], MK-571, and MK-679), as well as zileuton (A-64077, a direct inhibitor of 5-LO) have been developed as antiasthma agents. Clinical and experimental studies have demonstrated the efficacy of these compounds in reducing not only the symptoms of asthma, but use of beta 2-agonists and bronchoconstriction induced by exposure to allergens, exercise, aspirin, and cold air.