Pharmacokinetics Of Pf-00562271, A Focal Adhesion Kinase Inhibitor, In Patients With Advanced Non-Hematologic Malignancies

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 231 Focal adhesion kinase (FAK) transduces signaling from integrins and growth factors to modulate tumor cell invasion, proliferation and survival. PF-00562271, a potent FAK inhibitor, is under development as an anticancer agent. In the first-in-human, dose escalation trial, serial serum samples were collected to characterize single dose and steady-state pharmacokinetics (PK) of PF-00562271 after BID or QD oral dosing in patients with non-hematologic malignancies. Clinical safety and other outcome data from this study have been described previously (Siu L et al, Proc. ASCO, 2007). Serum PF-00562271 concentrations were determined using a validated HPLC-MA/MS method. The concentration-time data were analyzed by non-compartmental methods using WinNonlin (Pharsight®, CA). After the lead-in single dose, PF-562,271 was readily absorbed with the maximum serum concentration (Cmax) achieved between 0.5 to 5 hr; the increase in systemic exposure (AUCinf) was dose proportional at doses from 5 mg to 25 mg, but was more than dose proportional at higher doses. After repeated oral dosing, there was a more than proportional accumulation in the PF-00562271 steady-state exposure. The mean ratio of AUC during a dose interval at steady state (AUC0-τ,ss) to AUC0-inf after the lead-in dose ranged from 1.5 to 5.72, indicating a non-linear PK following repeated oral dosing. At the highest doses tolerated on an empty stomach of 80 mg BID and 175 mg QD, the average steady-state serum PF-00562271 concentrations were 29-fold and 46-fold, respectively, higher than the predicted efficacious concentration based on preclinical xenograft models. (W.G. Roberts, Cancer Res, 2008) In summary, the PK results demonstrated that PF-00562271 displayed a time- and dose-dependent non-linear PK, which is consistent with the in vitro observation of mechanism-based inhibition of the primary metabolic enzyme CYP 3A4 by PF-00562271. The PK results support both BID and QD regimens as viable options for further evaluation of PF-00562271 in Phase 2 studies. #