Population pharmacokinetics of trastuzumab emtansine (T-DM1), a HER2-targeted antibody–drug conjugate, in patients with HER2-positive metastatic breast cancer: clinical implications of the effect of covariates

Autor: Meghna Samant, Dan Lu, Joo Hee Yi, Pierfranco Conte, Melody A. Cobleigh, Yuying Gao, Bei Wang, Ellie Guardino, Sandhya Girish, Mothaffar F. Rimawi, Jin Yan Jin
Rok vydání: 2014
Předmět:
Oncology
Cancer Research
Receptor
ErbB-2
T-DM1
Pharmacology
Toxicology
chemistry.chemical_compound
ErbB-2
Trastuzumab
Monoclonal
Tissue Distribution
Pharmacology (medical)
skin and connective tissue diseases
Humanized
Ado-trastuzumab emtansine
HER2
Metastatic breast cancer
Pharmacokinetics
Antibodies
Monoclonal
Humanized
Antineoplastic Agents
Biological Availability
Breast Neoplasms
Enzyme-Linked Immunosorbent Assay
Female
Humans
Linear Models
Maytansine
Prognosis
United States
education.field_of_study
Original Article
Receptor
medicine.drug
musculoskeletal diseases
congenital
hereditary
and neonatal diseases and abnormalities
medicine.medical_specialty
Antibody-drug conjugate
medicine.drug_class
Population
Monoclonal antibody
Antibodies
Internal medicine
medicine
education
business.industry
medicine.disease
chemistry
Trastuzumab emtansine
business
Zdroj: Cancer Chemotherapy and Pharmacology
ISSN: 1432-0843
0344-5704
Popis: Purpose Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising the humanized monoclonal antibody trastuzumab linked to DM1, a highly potent cytotoxic agent. A population pharmacokinetic (PK) analysis was performed to estimate typical values and interindividual variability of T-DM1 PK parameters and the effects of clinically relevant covariates. Methods Serum samples were collected from 671 patients with human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer (MBC) who received single-agent T-DM1 in five phase I to phase III studies. Nonlinear mixed-effects modeling with the first-order conditional estimation method was used. Results A linear two-compartment model with first-order elimination from the central compartment described T-DM1 PKs in the clinical dose range. T-DM1 elimination clearance was 0.676 L/day, volume of distribution in the central compartment (Vc) was 3.127 L, and terminal elimination half-life was 3.94 days. Age, race, region, and renal function did not influence T-DM1 PK. Given the low-to-moderate effect of all statistically significant covariates on T-DM1 exposure, none of these covariates is expected to result in a clinically meaningful change in T-DM1 exposure. Conclusions T-DM1 PK properties are consistent and predictable in patients. A further refinement of dose based on baseline covariates other than body weight for the current 3.6 mg/kg regimen would not yield clinically meaningful reductions in interindividual PK variability in patients with MBC. Electronic supplementary material The online version of this article (doi:10.1007/s00280-014-2500-2) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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