PF-04449913 (Synonyms: Glasdegib)

Animal models

Rats and dogs

Dosage form

1 mg/kg and 0.5 mg/kg, Oral dosing

Application

In rats and dogs, PF-04449913 had high clearance in rat and low clearance in dog with CL of 31 and 3.9 mL/min/kg, respectively. The oral bioavailabilities of PF-04449913 in rat and dog were 33 and 68%, respectively. PF-04449913 had moderate volume distribution of 4.8 and 4.3 L/kg and t1/2 of 1.4 and 2.9 h, respectively.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

Disease models

Patients with advanced solid tumors

Dosage form

80 mg-640 mg, orally administered once daily, continuous 28-day

Application

In patients with advanced solid tumors, the first-cycle dose-limiting toxicity (DLT) rate at the 640 mg dose level was 33.3%, and the maximum tolerated dose (MTD) of PF-04449913 was estimated to be 320mg once daily. PF-04449913 was generally well tolerated at doses of 80 to 320 mg once daily. PF-04449913 modulated hedgehog signaling at the dose levels tested and downregulated GLI1 expression in the skin of patients by >80%.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1] Munchhof MJ, Li Q, Shavnya A, Borzillo GV, Boyden TL, Jones CS, LaGreca SD, Martinez-Alsina L, Patel N, Pelletier K, Reiter LA, Robbins MD, Tkalcevic GT. Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened. ACS Med Chem Lett. 2011 Dec 21;3(2):106-11.

[2]. Wagner AJ1, Messersmith WA2, Shaik MN3, et al. A phase I study of PF-04449913, an oral hedgehog inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2015 Mar 1;21(5):1044-51.