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.
Publication types
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Clinical Trial, Phase I
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Clinical Trial, Phase II
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Multicenter Study
MeSH terms
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Ado-Trastuzumab Emtansine
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Adult
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Antibodies, Monoclonal, Humanized / administration & dosage
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Antibodies, Monoclonal, Humanized / adverse effects
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Antibodies, Monoclonal, Humanized / pharmacokinetics*
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Aspartate Aminotransferases / blood
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Biomarkers, Tumor / immunology
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Biomarkers, Tumor / metabolism*
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Body Weight
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Breast Neoplasms / blood
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / immunology
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Breast Neoplasms / pathology
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Drug Administration Schedule
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Drug Dosage Calculations
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Female
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Humans
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Immunotoxins / administration & dosage
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Immunotoxins / adverse effects
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Immunotoxins / pharmacokinetics*
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Infusions, Intravenous
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Linear Models
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Maximum Tolerated Dose
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Maytansine / administration & dosage
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Maytansine / adverse effects
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Maytansine / analogs & derivatives*
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Maytansine / pharmacokinetics
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Middle Aged
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Models, Biological
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Protein Binding
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Receptor, ErbB-2 / immunology
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Receptor, ErbB-2 / metabolism*
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Serum Albumin / metabolism
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Trastuzumab
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Treatment Outcome
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Tubulin Modulators / administration & dosage
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Tubulin Modulators / adverse effects
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Tubulin Modulators / pharmacokinetics*
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Tumor Burden
Substances
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Antibodies, Monoclonal, Humanized
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Biomarkers, Tumor
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Immunotoxins
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Serum Albumin
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Tubulin Modulators
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Maytansine
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Aspartate Aminotransferases
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ERBB2 protein, human
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Receptor, ErbB-2
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Trastuzumab
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Ado-Trastuzumab Emtansine