Pharmacokinetic modeling and simulation (PK M&S) supported dose escalation of PF-03446962, a monoclonal antibody (mAb) against activin receptor like kinase 1, in patients with solid tumors.

2595 Background: PF-03446962 is a first in class mAb. The PK of mAbs is complex, as their clearance (CL) can be linear or non-linear, besides extremely slow. Caution must be exercised when designing mAbs’ dose escalation schemes. Along with safety and activity evaluation, we used PK M&S in real time to ensure that subsequent recommended doses did not expose too many patients to subtherapeutic levels while preserving safety. Methods: The model incorporated both Michaelis-Menten approximation and linear components. A prespecified target exposure was defined by preclinically projected therapeutic and toxic concentrations. The PK M&S results were used to make dose escalation decisions. Results: Eight dose levels (0.5, 1, 2, 3, 4.5, 6.75, 10, and 15 mg/kg) were studied in 44 patients. CL of PF-03446962 exhibited nonlinear characteristics at low doses and linear at high doses. CL was saturated at dose levels of 3 mg/kg and above. Mean half-life was 2.6 days for the first dose level and 12-15 days after CL satur...