Population pharmacokinetics and exposure–response analyses of trastuzumab in patients with advanced gastric or gastroesophageal junction cancer
Autor: | Vivian Ng, Michaela Lehle, Valerie Cosson, Bert L. Lum |
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Rok vydání: | 2014 |
Předmět: |
Adult
Male Oncology Cancer Research medicine.medical_specialty Esophageal Neoplasms Receptor ErbB-2 medicine.medical_treatment Population Serum albumin Antibodies Monoclonal Humanized Toxicology Deoxycytidine Young Adult Breast cancer Stomach Neoplasms Trastuzumab Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Humans Pharmacology (medical) education Capecitabine Survival analysis Aged Aged 80 and over Pharmacology Chemotherapy education.field_of_study biology business.industry Cancer Middle Aged medicine.disease Survival Analysis biology.protein Female Esophagogastric Junction Fluorouracil Cisplatin business Progressive disease medicine.drug |
Zdroj: | Cancer Chemotherapy and Pharmacology. 73:737-747 |
ISSN: | 1432-0843 0344-5704 |
Popis: | The aim of this study was to characterize trastuzumab population pharmacokinetics (PKs) in patients with human epidermal growth factor receptor 2-positive advanced gastric or gastroesophageal junction cancer and the relationship of trastuzumab PK with patient response. A nonlinear mixed effects PK model was built using data from the ToGA study. Patients were randomized to intravenous trastuzumab plus chemotherapy or chemotherapy alone. The influence of demographic, laboratory, and disease characteristics on PK parameters was assessed. An exploratory exposure–response analysis compared various PK parameters at steady state with best overall tumor response and overall survival (OS). Trastuzumab PK was best described by a two-compartment model with parallel linear and nonlinear (Michaelis–Menten) elimination from the central compartment. Total clearance (and half-life) of trastuzumab was concentration-dependent. Body weight, prior gastrectomy, and serum albumin had the greatest influence on trastuzumab PK; increasing weight and decreasing albumin levels were associated with increased clearance, while prior gastrectomy correlated with decreased clearance. Median values for AUC, C max, and C min were lower in patients with progressive disease (PD) than other response categories, although the 1.5 interquartile ranges overlapped. Patients with the lowest C min had the highest PD rate and a shorter OS. In the advanced gastric cancer population, trastuzumab PK was best described by a two-compartment model with parallel linear and nonlinear elimination. Predicted PK exposure was lower than previously reported for breast cancer. Patients with the lowest C min had a shorter OS and the highest PD rate, but a distinct correlation was not observed for tumor response. |
Databáze: | OpenAIRE |
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