Population pharmacokinetic (PK) analysis supports fixed dosing for the humanized monoclonal antibody (huMAb) anti-EGFL7 (MEGF0444A) administered intravenously in patients with advanced solid tumors.

Abstract

2586 Background: Monoclonal antibody therapeutics in oncology are most frequently dosed using body weight (BW)-based dosing, which may be due to the perception that BW-based dosing may be more precise. MEGF0444A is a huMAb that targets and inhibits the epidermal growth factor-like domain 7 (EGFL7) and has anti-vascular, and anti-re-growth effects on tumor vasculature and anti-tumor activity, particularly in combination with anti-VEGF. The objective of this analysis was to characterize MEGF0444A PK from two Phase I studies in patients (pts) with solid tumors and to evaluate the potential for using fixed dosing in Phase II studies. Methods: Noncompartment and population analyses were performed using pt data from the Phase Ia (0.3, 1, 3, 7.5, and 15 mg/kg q3wk) and Ib (2, 5, and 10 mg/kg q2wk) studies. Pt demographic data and other clinical relevant covariates were incorporated in the population analysis. PK simulation of 1000 subjects with a BW distribution was performed to compare the inter-individual variability of MEGF0444A exposure following fixed or BW-based dosing. Results: MEGF0444A was characterized by linear PK in the dose range tested. The clearance (CL) and volume of distribution (Vd) values were consistent with those of a typical huMAb. The elimination half-life was approximately 2 weeks. BW effect on CL and Vd was found to be minor to moderate, which appeared to be smaller when compared with other oncology MAbs. PK simulations suggest that fixed dosing may result in less inter-individual variability in MEGF0444A exposure compared with BW-based dosing. In addition, under- and over-exposure in extreme BW pts tended to be reduced with fixed dosing. Conclusions: PK characteristics support dosing of MEGF0444A every 2 or 3 weeks to maintain desired drug exposure. Population PK analysis results support fixed dosing of MEGF0444A at the equivalent 5 mg/kg q2 wk doses (400mg q2 or 600mg q3 wks) in future studies. The current analysis provides valuable insights on fixed dosing for oncology MAbs.