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Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer
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Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer
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Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer
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Journal Article
Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer
2012
Overview
Purpose
Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising trastuzumab and DM1, a microtubule polymerization inhibitor, covalently bound via a stable thioether linker. To characterize the pharmacokinetics (PK) of T-DM1 in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, data from four studies (TDM3569g, TDM4258g, TDM4374g, and TDM4688g) of single-agent T-DM1 administered at 3.6 mg/kg every 3 weeks (q3w) were assessed in aggregate.
Methods
Multiple analytes—T-DM1, total trastuzumab (TT), DM1, and key metabolites—were quantified using enzyme-linked immunosorbent assays or liquid chromatography tandem mass spectrometry. PK parameters of T-DM1, TT, and DM1 exposure were calculated using standard noncompartmental approaches and correlated to efficacy (objective response rate) and safety (platelet counts, hepatic transaminase concentrations). Immunogenicity was evaluated by measuring anti-therapeutic antibodies (ATA) to T-DM1 after repeated dosing using validated bridging antibody electrochemiluminescence or enzyme-linked immunosorbent assays.
Results
PK parameters for T-DM1, TT, and DM1 were consistent across studies at cycle 1 and steady state. T-DM1 PK was not affected by residual trastuzumab from prior therapy or circulating extracellular domain of HER2. No significant correlations were observed between T-DM1 exposure and efficacy, thrombocytopenia, or increased concentrations of transaminases. Across the studies, ATA formation was detected in 4.5% (13/286) of evaluable patients receiving T-DM1 q3w.
Conclusions
The PK profile of single-agent T-DM1 (3.6 mg/kg q3w) is predictable, well characterized, and unaffected by circulating levels of HER2 extracellular domain or residual trastuzumab. T-DM1 exposure does not correlate with clinical responses or key adverse events.
Publisher
Springer-Verlag,Springer,Springer Nature B.V
Subject
/ Adult
/ Aged
/ Antibodies, Monoclonal, Humanized - pharmacokinetics
/ Antibodies, Monoclonal, Humanized - pharmacology
/ Antibodies, Monoclonal, Humanized - therapeutic use
/ Biological and medical sciences
/ Breast Neoplasms - drug therapy
/ Breast Neoplasms - pathology
/ Enzyme-Linked Immunosorbent Assay
/ Epidermal growth factor receptors
/ Female
/ Gynecology. Andrology. Obstetrics
/ Humans
/ Liver
/ Maytansine - analogs & derivatives
/ Maytansine - pharmacokinetics
/ Maytansine - therapeutic use
/ Medicine
/ Oncology
/ Original
/ Pharmacology. Drug treatments
/ Receptor, ErbB-2 - metabolism
/ Tumors
