Abstract
2525 Background: rhApo2L/TRAIL induces apoptosis through binding to the pro-apoptotic receptors DR4 and DR5. This drug selectively induces apoptosis in many cancer cell lines derived from various malignancies, while sparing most normal cells in preclinical models. Preclinically, clearance of this molecule was highly correlated with glomerular filtration rate (GFR), suggesting that the kidney could play a critical role in elimination. Body weight-normalized doses were selected for the first-in-human study. This population PK analysis (PPK) and covariate analysis was conducted to: 1) describe the PK of rhApo2L/TRAIL using a non-linear mixed effects modeling approach and 2) identify covariates as potential predictors of PK variability. Methods: The NONMEM analysis was performed using 1034 serum concentration samples from 67 patients receiving rhApo2L/TRAIL at doses ranging from 0.5–30 mg/kg. Potentially clinically relevant covariates were evaluated. Results: A one-compartment model with linear clearance best described rhApo2L/TRAIL concentration data. After the inclusion of the statistically significant covariates (CRCL on CL and weight on Vd), the typical parameter estimates (percent of standard error of estimation) of rhApo2L/TRAIL clearance (CL) and volume of distribution (Vd) were 116 L/day (3.85%) and 4.28 L (3.69%), respectively. The inter-patient variability (IIV) for CL and Vd was 32.6% (19.3%) and 27.9% (28.6%), respectively. Creatinine clearance explained the IIV of CL by 26.4% and weight explained the IIV of Vd by 25%. Gender, age, race, albumin, alkaline phosphatase, and aspartate aminotransferase had no effect on rhApo2L/TRAIL PK. Conclusions: A one-compartment model with linear clearance accurately described rhApo2L/TRAIL PK disposition in patients in this trial. Creatinine clearance and weight marginally reduced inter-individual variability of rhApo2L/TRAIL. Further assessments of additional variables likely to play a role in clearance and the necessity of weight-based dosing are ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech™ BioOncology Genentech™ BioOncology Genentech™ BioOncology Genentech™ BioOncology Genentech™ BioOncology Genentech™ BioOncology
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