The Bcl-2 Family Inhibitor ABT-263 Shows Significant but Reversible Thrombocytopenia in Mice.

ABT-263 is an orally bioavailable small molecule inhibitor of Bcl-2 family proteins with a K_i of ≤ 1 nM against Bcl-2, Bcl-X_L, and Bcl-w. Potent cytotoxic effects have been demonstrated against small cell lung carcinomas and lymphomas (EC₅₀ of less than 500 nM in vitro against numerous cell lines). Tumor growth stasis and regression in xenograft models confirmed this activity. However, a unique thrombocytopenia has been observed in mice, rats, and dogs. Using a mouse model to characterize the extent and duration of decreased circulating platelets, outbred CF-1 or inbred scid-bg mice were treated with increasing doses of ABT-263. Blood samples were collected at various times post dosing and platelet numbers were determined using automated hematology analysis. The results showed a rapid, dose-dependent reduction in circulating platelet counts with a platelet nadir (>80% reduction relative to baseline) occurring approximately 6 hours after a single 100 mg/kg oral dose of ABT-263. Platelet counts returned to normal levels by 72 hrs post-dose. Analysis of bleeding times using a tail-nick method demonstrated a correlation between reduced platelet count and increased bleeding time. At doses of 50 mg/kg and higher, bleed times were increased by more than 5-fold relative to vehicle controls. In multi-dose studies, platelet levels did not continue to decline relative to the first dose of ABT-263. Mice treated with ABT-263 at 100 mg/kg/day for as long as 21 days exhibited no overt signs of toxicity (bleeding, significant weight loss, etc). Because the spleen is a potential site for clearing of damaged or aggregated platelets, a study using splenectomized mice was also conducted. The kinetics of platelet reduction and recovery were similar in splenectomized vs. intact mice with no additional adverse events noted. Evaluations of plasma drug levels associated with preclinical anti-tumor efficacy vs. thrombocytopenic effects indicate that a reasonable therapeutic window exists for ABT-263.