Interpretation of BDH for Drug Development

BDH can progress to cholangiocarcinoma with low margin of safety, a scenario that can lead to costly, late stage compound terminations and increased risk to patient safety. On the other hand, progression of BDH to neoplasia is not a certainty; at least one blockbuster medication (Lipitor®) is taken chronically by patients to reduce cholesterol, in spite of the fact that this compound caused BDH at 3 months or less in both rats and dogs (NDA 20-702). Interpretation of the significance of BDH therefore requires consideration of a number of variables, including duration of exposure, margin of safety, intended patient population, and availability of biomarkers to monitor patient safety.

Many compounds cause BDH after just a few days of once daily dosing. In such instances it is reasonable to expect that with greater duration of exposure BDH will progress in severity and become observable at lower doses, leading to decreased margin of safety in GLP studies that support clinical trials. Because progression of BDH with extended treatment contributes to compound attrition during drug development, methods to identify compounds that do not cause BDH, or with improved margin of safety, are desirable. Ideally this would be an in vitro screen that is predictive of the in vivo response.

Considerable effort has been made to develop in vitro culture techniques for biliary epithelial cells, including their use in screening assays (Gall and Bhathal, 1987; Couchie et al., 2002; Suzuki et al., 2002; Yin et al., 2002; Qin et al., 2004). This work has improved our understanding of oval cells and other hepatic progenitor cell populations, but an in vitro assay to screen compounds for their ability to cause BDH has yet to be reported. Several factors are likely operative in limiting the success of in vitro BDH assays, including failure of progenitor cells to proliferate and differentiate in culture, and inability of primary cells to metabolize xenobiotics. In addition, since BDH occurs in some instances due to signals emanating from physical obstruction of the bile duct or bile cannaliculi, culture models may not accurately replicate some pathophysiological events that are important in the etiology of BDH.

The desire to identify compounds that do not cause BDH, and the lack of adequate models to screen compounds in vitro, requires testing additional compounds in vivo. This strategy can be successful when the incidence of BDH in the structural series is reasonably low. If, however, the incidence of BDH in the structural series is high, or the lesion does not appear until prolonged exposure, the need to screen multiple compounds in vivo can result in significant delays or even program termination. Thus, drug developers need an alternative strategy, such as a biomarker that predicts outcome of long-term exposures. Such biomarkers would be useful not only for pre-clinical toxicology testing, but also to support clinical drug development.

Currently there is a substantial difference in the availability of in vivo biomarkers of BDH for the two mechanisms that lead to compound-induced BDH. Changes in liver function associated with the cholestasis mechanism can be monitored pre-clinically and clinically using serological biomarkers such as total bilirubin concentration, alkaline phosphatase activity, and 7-glutamyl-transpep-tidase activity (Smith et al., 2002). Consequently, development of compounds that cause BDH through a cholestatic mechanism is supported by well-validated serological biomarkers. In contrast, BDH induced via oval cell proliferation is a toxicological endpoint for which drug developers do not have biomarkers to support clinical or pre-clinical drug development. Instead, we are limited to histology of biopsy tissue to monitor this pathogenesis. As a result, development of compounds that cause BDH is more challenging for molecules that cause oval cell proliferation than for compounds that cause cholestasis. Biomarkers to monitor or predict oval cell proliferation would therefore be of value to drug developers, both to screen compounds during LO and to minimize risk to patients during clinical development.

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