| 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 (Vc), 3.33 L (13.2%); peripheral compartment volume (Vp), 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 Vc 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. © 2012 The Author(s). |
| Keywords: |
adult; treatment outcome; middle aged; major clinical study; pathophysiology; linear models; demography; metastasis; breast cancer; models, biological; tumor volume; drug administration schedule; epidermal growth factor receptor 2; tumor markers, biological; protein binding; body weight; breast neoplasms; aspartate aminotransferase blood level; aspartate aminotransferase; albumin; tumor burden; drug clearance; receptor, erbb-2; maximum tolerated dose; trastuzumab; infusions, intravenous; tubulin modulators; maytansine; compartment model; serum albumin; drug dosage calculations; immunotoxins; trastuzumab emtansine; antibodies, monoclonal, humanized; antibody-drug conjugate; population pharmacokinetics; t-dm1; aspartate aminotransferases
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