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 (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.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.019182.
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ABBREVIATIONS: ADEPT, antibody-directed enzyme prodrug therapy; PBPK, physiologically based pharmacokinetic model; GA, geldanamycin; FcRn, neonatal Fc-receptor; AbE, antibody-enzyme conjugates; TAG-72, tumor-associated glycoprotein 72; PA, effective permeability coefficients; AUC, area under the curve; PK, pharmacokinetics; PD, pharmacodynamics; Tau, time interval between AbE and prodrug.
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↵1 Current affiliation: Clinical DMPK, Merck & Co., Inc., West Point, PA.
- Received October 10, 2007.
- Accepted March 19, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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