Modeling the efficacy of trastuzumab-DM1, an antibody drug conjugate, in mice.
Trastuzumab-DM1 (T-DM1) is a novel antibody-drug conjugate under investigation for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. One challenge in oncologic drug development is determining the optimal dose and treatment schedule. A novel dose regimen-finding strategy was developed for T-DM1 using experimental data and pharmacokinetic/pharmacodynamic modeling. To characterize the disposition of T-DM1, pharmacokinetic studies were conducted in athymic nude and beige nude mice. The pharmacokinetics of T-DM1 were described well by a two-compartment model. Tumor response data were obtained from single-dose, multiple-dose and time-dose-fractionation studies of T-DM1 in animal models of HER2-positive breast cancer, specifically engineered to be insensitive to trastuzumab. A sequential population-based pharmacokinetic/pharmacodynamic modeling approach was developed to describe the anti-tumor activity of T-DM1. A cell-cycle-phase nonspecific tumor cell kill model incorporating transit compartments captured well the features of tumor growth and the activity of T-DM1. Key findings of the model were that tumor cell growth rate played a significant role in the sensitivity of tumors to T-DM1; anti-tumor activity was schedule independent; and tumor response was linked to the ratio of exposure to a concentration required for tumor stasis.
Jumbe
Nelson L
NL
Department of Pharmacokinetics, Pharmacodynamics, and Bioanalytical Sciences, Genentech, Inc., 1 DNA Way, MS463, South San Francisco, CA 94080, USA.
Xin
Yan
Y
Leipold
Douglas D
DD
Crocker
Lisa
L
Dugger
Debra
D
Mai
Elaine
E
Sliwkowski
Mark X
MX
Fielder
Paul J
PJ
Tibbitts
Jay
J
D000080044:Ado-Trastuzumab Emtansine; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D008453:Maytansine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D013997:Time Factors; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000922:Immunotoxins; D008453:Maytansine; D000068878:Trastuzumab; D000080044:Ado-Trastuzumab Emtansine