title: Mechanistic pharmacokinetic/pharmacodynamic modeling of in vivo tumor uptake, catabolism, and tumor response of trastuzumab maytansinoid conjugates.
abstract: OBJECTIVE
  Trastuzumab emtansine (T-DM1), an antibody-drug conjugate (ADC) comprised of trastuzumab linked to the antimitotic agent DM1, has shown promising results in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. Investigations of the mechanisms of the action of ADCs, including T-DM1, have been primarily descriptive or semiquantitative. However, quantitative pharmacokinetic/pharmacodynamic (PK/PD) analysis may provide insights into their complex behavior. The analyses described herein applied PK/PD modeling to nonclinical studies of maytansinoid conjugates.
  
  
  METHODS
  The maytansinoid conjugates T-DM1 and T-SPP-DM1, with thioether and disulfide linkers, respectively, were tested in mouse efficacy, PK, and tumor uptake studies. (3)[H]DM1-bearing ADCs were used to facilitate the quantitation of the ADCs in plasma, as well as ADC and ADC catabolites in tumors. Three mechanistic PK/PD models were used to characterize plasma ADC, tumor ADC, and tumor catabolite concentrations. Tumor catabolite concentrations were used to fit tumor response. Model parameters were estimated using R software and nonlinear least squares regression.
  
  
  RESULTS
  Plasma ADC-associated DM1 concentrations of T-DM1 decreased more slowly than those of T-SPP-DM1, likely due to slower DM1 release. A comparison of the mechanistic models found that the best model allowed catabolism and catabolite exit rates to differ between ADCs, that T-DM1 exhibited both faster tumor catabolism and catabolite exit rate from tumors than T-SPP-DM1; findings inconsistent with expected behavior based on the physicochemical nature of the respective catabolites. Tumor catabolite concentrations adequately described tumor response with both ADCs showing similar potency.
  
  
  CONCLUSIONS
  Mechanistic PK/PD studies described herein provided results that confirmed and challenged current hypotheses, and suggested new areas of investigation.
authors.affiliation: Quantitative Solutions, Menlo Park, CA, USA.
authors.forename: Russ
authors.initials: R
authors.lastname: Wada
authors.forename: Hans K
authors.initials: HK
authors.lastname: Erickson
authors.forename: Gail D
authors.initials: GD
authors.lastname: Lewis Phillips
authors.forename: Carmela A
authors.initials: CA
authors.lastname: Provenzano
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Leipold
authors.forename: Elaine
authors.initials: E
authors.lastname: Mai
authors.forename: Holly
authors.initials: H
authors.lastname: Johnson
authors.forename: Jay
authors.initials: J
authors.lastname: Tibbitts
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000465:Algorithms; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008453:Maytansine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D008819:Mice, Nude; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D000068878:Trastuzumab; D016896:Treatment Outcome; D014316:Tritium
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014316:Tritium; D008453:Maytansine; D000068878:Trastuzumab; D000080044:Ado-Trastuzumab Emtansine