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

Division of Pharmaceutics, College of Pharmacy, the Ohio State University, Columbus, Ohio

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 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 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.