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 Journal Article


Authors: Gupta, M.; LoRusso, P. M.; Wang, B.; Yi, J. H.; Burris, H. A.; Beeram, M.; Modi, S.; Chu, Y. W.; Agresta, S.; Klencke, B.; Joshi, A.; Girish, S.
Article 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 (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
Journal Title: Journal of Clinical Pharmacology
Volume: 52
Issue: 5
ISSN: 0091-2700
Publisher: Sage Publications  
Date Published: 2012-05-01
Start Page: 691
End Page: 703
Language: English
DOI: 10.1177/0091270011403742
PROVIDER: scopus
PUBMED: 21953571
DOI/URL:
Notes: --- - "Export Date: 4 June 2012" - "CODEN: JCPCB" - "Source: Scopus"
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  1. Shanu Modi
    171 Modi