Application of PBPK modeling to predict monoclonal antibody disposition in plasma and tissues in mouse models of human colorectal cancer
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This investigation evaluated the utility of a physiologically based pharmacokinetic (PBPK) model, which incorporates model parameters representing key determinants of monoclonal antibody (mAb) target-mediated disposition, to predict, a priori, mAb disposition in plasma and in tissues, including tumors that express target antigens. Monte Carlo simulation techniques were employed to predict the disposition of two mAbs, 8C2 (as a non-binding control mouse IgG1 mAb) and T84.66 (a high-affinity murine IgG1 anti-carcinoembryonic antigen mAb), in mice bearing no tumors, or bearing colorectal HT29 or LS174T xenografts. Model parameters were obtained or derived from the literature. 125I-T84.66 and 125I-8C2 were administered to groups of SCID mice, and plasma and tissue concentrations were determined via gamma counting. The PBPK model well-predicted the experimental data. Comparisons of the population predicted versus observed areas under the plasma concentration versus time curve (AUC) for T84.66 were 95.4 ± 67.8 versus 84.0 ± 3.0, 1,859 ± 682 versus 2,370 ± 154, and 5,930 ± 1,375 versus 5,960 ± 317 (nM × day) at 1, 10, and 25 mg/kg in LS174T xenograft-bearing SCID mice; and 215 ± 72 versus 233 ± 30, 3,070 ± 346 versus 3,120 ± 180, and 7,884 ± 714 versus 7,440 ± 626 in HT29 xenograft-bearing mice. Model predicted versus observed 8C2 plasma AUCs were 312.4 ± 30 versus 182 ± 7.6 and 7,619 ± 738 versus 7,840 ± 24.3 (nM × day) at 1 and 25 mg/kg. High correlations were observed between the predicted median plasma concentrations and observed median plasma concentrations (r 2 = 0.927, for all combinations of treatment, dose, and tumor model), highlighting the utility of the PBPK model for the a priori prediction of in vivo data.
KeywordsMonoclonal antibody Target-mediated disposition (TMD) Physiologically based pharmacokinetic (PBPK) Monte Carlo simulation Preclinical pharmacokinetic Tissue disposition
This work was supported by funding from the Center for Protein Therapeutics and from the National Cancer Institute of the National Institutes of Health (CA114612).
- 27.Chen J, Balthasar JP (2007) Development and characterization of high affinity anti-topotecan IgG and Fab fragments. In: Gad SC (ed) Handbook of pharmaceutical biotechnology. Wiley, Hoboken, pp 835–850Google Scholar
- 34.Esteban JM, Kuhn JA, Felder B, Wong JY, Battifora H, Beatty JD, Wanek PM, Shively JE (1991) Carcinoembryonic antigen expression of resurgent human colon carcinoma after treatment with therapeutic doses of 90Y-alpha-carcinoembryonic antigen monoclonal antibody. Cancer Res 51:3802–3806PubMedGoogle Scholar
- 40.Wagener C, Clark BR, Rickard KJ, Shively JE (1983) Monoclonal antibodies for carcinoembryonic antigen and related antigens as a model system: determination of affinities and specificities of monoclonal antibodies by using biotin-labeled antibodies and avidin as precipitating agent in a solution phase immunoassay. J Immunol 130:2302–2307PubMedGoogle Scholar
- 43.Pastuskovas CV, Mundo EE, Williams SP, Nayak TK, Ho J, Ulufatu S, Clark S, Ross S, Cheng E, Parsons-Reponte K, Cain G, Van Hoy M, Majidy N, Bheddah S, Dela Cruz Chuh J, Kozak KR, Lewin-Koh N, Nauka P, Bumbaca D, Sliwkowski M, Tibbitts J, Theil FP, Fielder PJ, Khawli LA, Boswell CA (2012) Effects of Anti-VEGF on Pharmacokinetics, Biodistribution, and Tumor Penetration of Trastuzumab in a Preclinical Breast Cancer Model. Mol Cancer Ther 11:752–762PubMedCrossRefGoogle Scholar
- 47.US Food and Drug Administration (FDA) (2011) Label for Avastin (bevacizumab). http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125085s0168lbl.pdf. Accessed April 2011