Predictive physiologically based pharmacokinetic model for antibody-directed enzyme prodrug therapy.
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.
Fang
Lanyan
L
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 W 12th Ave, Columbus, OH 43210, USA.
Sun
Duxin
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000276:immunology; D019540:Area Under Curve; D016227:Benzoquinones / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy*; D006023:Glycoproteins / Q000276:immunology; D018796:Immunoconjugates / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D047029:Lactams, Macrocyclic / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051379:Mice; D008954:Models, Biological; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D016227:Benzoquinones; D006023:Glycoproteins; D018796:Immunoconjugates; D047029:Lactams, Macrocyclic; D011355:Prodrugs; C047052:tumor-associated antigen 72; C001277:geldanamycin