Predictive Physiologically Based Pharmacokinetic Model for Antibody-Directed Enzyme Prodrug Therapy

Abstract

Antibody-directed enzyme prodrug therapy (ADEPT) using anti-TAG-72 antibody and geldanamycin (GA) prodrug were validated in vitro. To understand the complexity and to explore optimal therapeutic regimens for ADEPT in vivo, a physiologically based pharmacokinetic model (PBPK) is applied to analyze each anatomical component/organ. The baseline model predicts that active drug tumor/plasma exposure (AUC) ratio is 2-fold, although antibody-enzyme conjugates (AbE) are distributed into tumors up to 9-fold higher than in plasma. However, the active drug tumor/plasma AUC ratio can be increased up to 100-fold when AbE are depleted from plasma. Similarly, the active drug tumor/plasma AUC ratio can be increased from 2- to 6-fold when the intrinsic clearance of AbE is accelerated by 10-fold. Several sensitive parameters are identified: 1) increasing flow inside tumor (J(iso,tumor)) significantly increases active drug tumor/plasma AUC ratio; 2) increasing permeability of prodrug (from range 1.4 x 10(-6) to 1.4 x 10(-4) cm/s) increases active drug tumor/plasma AUC ratio significantly, whereas active drug permeability enhancement (from range 5 x 10(-4) to 5 x 10(-2) cm/s) has minimal effect; 3) decreasing E(max) and increasing EC(50) for converting prodrug to active drug increase tumor/plasma AUC ratio for active drug. The PBPK model predicts that the optimal dosing interval between AbE and prodrug administration is 5 days, the optimal AbE dose is 0.1 B(max), and the optimal dose for GA prodrug is 60 mg/kg. The current PBPK model successfully identifies sensitive parameters and predicts an optimal dosing regimen for ADEPT.