title: Clinical implications of pathophysiological and demographic covariates on the population pharmacokinetics of trastuzumab emtansine, a HER2-targeted antibody-drug conjugate, in patients with HER2-positive metastatic breast cancer.
abstract: Trastuzumab emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate in development for treatment of HER2-positive cancers. T-DM1 has been tested as a single agent in a phase I and 2 phase II studies of patients with heavily pretreated metastatic breast cancer (MBC), with the maximum tolerated dose established at 3.6 mg/kg intravenously for every-3-week dosing. The authors present results from the population pharmacokinetics analysis for T-DM1. Population pharmacokinetics for T-DM1 were characterized using a clinical database of 273 patients from the 3 studies. Pharmacokinetics was best described by a linear 2-compartment model. Population estimates (interindividual variability [IIV]) for pharmacokinetic parameters were clearance, 0.7 L/d (21.0%); central compartment volume (V(c)), 3.33 L (13.2%); peripheral compartment volume (V(p)), 0.89 L (50.4%); and intercompartmental clearance, 0.78 L/d. Body weight, albumin, tumor burden, and aspartate aminotransferase levels were identified as statistically significant covariates accounting for interindividual variability in T-DM1 pharmacokinetics, with body weight having a greater effect on IIV of clearance and V(c) than other covariates. T-DM1 exposure was relatively consistent across the weight range following body weight-based dosing. This analysis suggests no further T-DM1 dose adjustments are necessary in heavily pretreated patients with MBC.
authors.affiliation: Genentech, Inc, South San Francisco, CA 94080, USA. manishg@gene.com
authors.forename: Manish
authors.initials: M
authors.lastname: Gupta
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Lorusso
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.forename: Joo-Hee
authors.initials: JH
authors.lastname: Yi
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: Muralidhar
authors.initials: M
authors.lastname: Beeram
authors.forename: Shanu
authors.initials: S
authors.lastname: Modi
authors.forename: Yu-Waye
authors.initials: YW
authors.lastname: Chu
authors.forename: Samuel
authors.initials: S
authors.lastname: Agresta
authors.forename: Barbara
authors.initials: B
authors.lastname: Klencke
authors.forename: Amita
authors.initials: A
authors.lastname: Joshi
authors.forename: Sandhya
authors.initials: S
authors.lastname: Girish
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001219:Aspartate Aminotransferases / Q000097:blood; D014408:Biomarkers, Tumor / Q000276:immunology / Q000378:metabolism*; D001835:Body Weight; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D016014:Linear Models; D020714:Maximum Tolerated Dose; D008453:Maytansine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008875:Middle Aged; D008954:Models, Biological; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D012709:Serum Albumin / Q000378:metabolism; D000068878:Trastuzumab; D016896:Treatment Outcome; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D047368:Tumor Burden
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D001219:Aspartate Aminotransferases; D014408:Biomarkers, Tumor; D000922:Immunotoxins; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D012709:Serum Albumin; D000068878:Trastuzumab; D050257:Tubulin Modulators; C508053:ERBB2 protein, human