Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois.

ABT-737 and ABT-263 are small molecule inhibitors of Bcl-2 family proteins with sub-nanomolar affinities against Bcl-2, Bcl-XL, and Bcl-w. ABT-263 exhibits tumor regression activity in multiple preclinical murine xenograft cancer models and is currently in clinical development. The primary preclinical toxicological finding in mouse, rat and dog was a unique thrombocytopenia characterized by a rapid clearance of circulating platelets that appears to be the direct result of inhibition of Bcl-2 family proteins. A series of in vivo studies that were performed to better characterize this phenomenon are described here. After a single intravenous or oral dose in dogs, circulating platelet counts decreased rapidly and concentration-dependently with a nadir at approximately six hours post administration. Platelet counts returned to near normal levels within several days post dose, accompanied by an increase in both mean platelet volume and percent of reticulated platelets. Analysis of platelets by aggregometry during this rebound period indicated that returning platelets were fully functional. During chronic administration, platelet counts also decreased rapidly after initial dosing, but exhibited evidence of rebound during the dosing period that appeared to be dose-dependant. Evaluation of fibrinogen, d-dimer, antithrombin-III, PT and APTT did not support a mechanism involving consumptive coagulopathy. Whole body scintography utilizing [111] Indium labeled platelets in dogs indicated that the liver primarily mediates platelet clearance after compound administration. These data suggest that ABT-263 preferentially affects circulating platelets rather than abrogating platelet production in the bone marrow. A less active enantiomer control had no effect on circulating platelets in animals suggesting an underlying mechanism that is dependent on inhibition of antiapoptotic Bcl-2 family proteins. The unusually rapid kinetics of platelet clearance and recovery suggests that the drug-induced thrombocytopenia elicited by these Bcl-2 family protein inhibitors is distinct from that observed with conventional cytotoxic chemotherapy.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA