PT  - JOURNAL ARTICLE
AU  - Lanyan Fang
AU  - Duxin Sun
TI  - Predictive Physiologically Based Pharmacokinetic Model for Antibody-Directed Enzyme Prodrug Therapy
AID  - 10.1124/dmd.107.019182
DP  - 2008 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 1153--1165
VI  - 36
IP  - 6
4099  - http://dmd.aspetjournals.org/content/36/6/1153.short
4100  - http://dmd.aspetjournals.org/content/36/6/1153.full
SO  - Drug Metab Dispos2008 Jun 01; 36
AB  - 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 (Jiso,tumor) significantly increases active drug tumor/plasma AUC ratio; 2) increasing permeability of prodrug (from range 1.4 × 10–6 to 1.4 × 10–4 cm/s) increases active drug tumor/plasma AUC ratio significantly, whereas active drug permeability enhancement (from range 5 × 10–4 to 5 × 10–2 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 5 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 an optimal dosing regimen for ADEPT. The American Society for Pharmacology and Experimental Therapeutics