Received for publication October 10, 2007.
Revised March 19, 2008.
Accepted for publication March 19, 2008.

Predictive Physiologically-Based Pharmacokinetic (PBPK) Model for Antibody-Directed Enzyme Prodrug Therapy (ADEPT)

Abstract

Antibody-directed enzyme prodrug therapy (ADEPT) using anti-TAG-72 antibody and Geldanamycin (GA) prodrug was 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 tumor 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 1.4X10^-6 to 1.4X10^-4 cm/s) increases active drug tumor/plasma AUC ratio significantly, while active drug permeability enhancement (from range 5X10^-4 to 5X10^-2 cm/s) has minimal effect; 3) decreasing Emax and increasing EC50 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 five days, the optimal AbE dose is 0.1 Bmax, and the optimal dose for GA prodrug is 60 mg/kg. The current PBPK model successfully identifies sensitive parameters and predicts optimal dosing regimen for ADEPT.

Key words: antibodies, anticancer agents, drug distribution, drug targeting, pharmacokinetic modeling, pharmacokinetics