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Cetuximab pharmacokinetics

Ya-Jen Chang, Chung-Li Ho, Kai-Hung Cheng, Wan-I Kuo, Wan-Chi Lee, Keng-Li Lan, Chih-Hsien Chang
Background Cetuximab is a fully humanized IgG1 subclass monoclonal that binds specifically to the human epidermal growth factor receptor (EGFR). Although EGFR is expressed in normal cells, the overexpression of EGFR is detected in many human cancers, such as colon, rectum and lung tumors. In this study, cetuximab with a combination of radiotherapy nuclear 188 Re achieved better therapeutic effect on lung cancer. Methods188 Re-cetuximab administered by the i.v. route in human NCI-H292 lung tumor-bearing mice was investigated...
January 5, 2019: Investigational New Drugs
Haitham AlRabiah, Mohammed A Hamidaddin, Ibrahim A Darwish
This study describes, for the first time, the development of an automated sensitive flow fluorescent noncompetitive immunoassay based on kinetic-exclusion analysis (KinExA) for the quantitative determination of human plasma levels of monoclonal antibodies (mAbs) used for cancer immunotherapy. The assay was adapted on KinExA™ 3200 biosensor and optimized and validated for bevacizumab (BEV) and cetuximab (CET), as representative examples of the mAbs, using their specific antigens. These antigens were the human vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) for BEV and CET, respectively...
January 15, 2019: Talanta
Magnus T Dillon, Lorna Grove, Katie L Newbold, Heather Shaw, Nicholas F Brown, Jeanne Mendell, Shuquan Chen, Robert A Beckman, Anne Jennings, Marivic Ricamara, Jonathan Greenberg, Martin Forster, Kevin J Harrington
BACKGROUND: Patritumab plus cetuximab with platinum as first-line therapy for patients with recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) was evaluated for safety and to determine the recommended phase-II combination dose. METHODS: Patients aged ≥18 years with confirmed R/M SCCHN received intravenous patritumab (18-mg/kg loading dose [LD]); 9-mg/kg maintenance dose [MD] every 3 weeks [q3w]) + cetuximab (400-mg/m2 LD; 250-mg/m2 MD weekly) + cisplatin (100 mg/m2 q3w) or carboplatin (area under the curve [AUC] of 5) for 6 cycles or until toxicity, disease progression, or withdrawal...
October 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Mohammed A Hamidaddin, Haitham AlRabiah, Ibrahim A Darwish
This study describes, for the first time, the development and validation of a highly selective and sensitive heterogeneous fluoroimmunoassay (FIA) for the bioanalysis of two monoclonal antibodies (mAbs) used for cancer immunotherapy: bevacizumab (BEV) and cetuximab (CET). The assay combines reliable non-competitive binding of BEV and CET to their specific cell receptor proteins (human vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), respectively) with the highly specific fluorescence activity of the fluorescein isothiocyanate labeled anti-human IgG (FITC-IgG) used as label...
October 1, 2018: Talanta
Min-Ho Park, Jin-Ju Byeon, Seok-Ho Shin, Nahye Kim, Yuri Park, Byeong Ill Lee, Jangmi Choi, Young G Shin
RATIONALE: The cassette-dosing technique is a technique that administers various drugs to a single animal at once and quantitated simultaneously. The purpose of this study was to evaluate the feasibility of cassette-dosing as a means of increasing throughput and decreasing animal usage for pharmacokinetic studies of biopharmaceuticals using liquid chromatography/time-of-flight mass spectrometric (LC/TOF-MS) analysis. METHODS: Brentuximab, trastuzumab, cetuximab and adalimumab were used as model biopharmaceuticals...
June 15, 2018: Rapid Communications in Mass Spectrometry: RCM
Luca Mazzarella, Alessandro Guida, Giuseppe Curigliano
Epidermal Growth Factor Receptor (EGFR)-dependent signaling plays a crucial role in epithelial cancer biology, and dictated the development of several targeting agents. The mouse-human chimeric antibody Cetuximab was among the first to be developed. After about two decades of clinical research it has gained a significant place in the management of advanced colorectal and head and neck cancers, whereas its development in non small cell lung cancer (NSCLC) has not led to a place in routine clinical practice, because of marginal clinical benefit despite statistically significant Phase III trials...
April 2018: Expert Opinion on Biological Therapy
Walter Fiedler, Sara Cresta, Henning Schulze-Bergkamen, Sara De Dosso, Jens Weidmann, Anna Tessari, Hans Baumeister, Antje Danielczyk, Bruno Dietrich, Steffen Goletz, Alfredo Zurlo, Marc Salzberg, Cristiana Sessa, Luca Gianni
Background: Changes in glycosylation of the constant domain (Fc) of monoclonal antibodies (mAbs) enhance antibody-dependent cell-mediated cytotoxicity independently of downstream effects following receptor blockade by the antibody, thus extending their indication. We investigated the safety, pharmacokinetics, pharmacodynamics and antitumour activity of tomuzotuximab, an IgG1 glycoengineered mAb against the epidermal growth factor receptor with enhanced tumour cytotoxicity in a phase I dose-escalation study (NTC01222637)...
2018: ESMO Open
Eva Pérez-Rodríguez, Juan Antonio Martínez-Tadeo, Natalia Pérez-Rodríguez, Guacimara Hernández-Santana, Ariel Callero-Viera, Elena Rodríguez-Plata, José Carlos García-Robaina
BACKGROUND: Hypersensitivity reactions to chemotherapy drugs are quite frequent. Desensitization for chemotherapy drugs has become an option to maintain first-line therapy in patients who have suffered such reactions. OBJECTIVE: The objective of this study was to describe our experience in desensitization with antineoplastic agents using a rapid 1-solution protocol. METHODS: We performed a 3-year prospective observational study recording all patients who were desensitized with this protocol...
September 2018: Journal of Allergy and Clinical Immunology in Practice
Outi Keinänen, Kimberly Fung, Jacob Pourat, Vilma Jallinoja, Delphine Vivier, NagaVara Kishore Pillarsetty, Anu J Airaksinen, Jason S Lewis, Brian M Zeglis, Mirkka Sarparanta
BACKGROUND: Pretargeting-based approaches are being investigated for radioimmunoimaging and therapy applications to reduce the effective radiation burden to the patient. To date, only a few studies have used short-lived radioisotopes for pretargeting of antibodies, and such examples with internalizing antibodies are even rarer. Herein, we have investigated pretargeting methodology using inverse electron-demand Diels-Alder (IEDDA) for tracing two clinically relevant, internalizing monoclonal antibodies, cetuximab and trastuzumab...
December 2, 2017: EJNMMI Research
Maya Sreeranganathan, Saji Uthaman, Bruno Sarmento, Chethampadi Gopi Mohan, In-Kyu Park, Rangasamy Jayakumar
Epidermal growth factor receptor (EGFR), upregulated in gastric cancer patients, is an oncogene of interest in the development of targeted cancer nanomedicines. This study demonstrates in silico modeling of monoclonal antibody cetuximab (CET MAb)-conjugated docetaxel (DOCT)-loaded poly(γ-glutamic acid) (γ-PGA) nanoparticles (Nps) and evaluates the in vitro/in vivo effects on EGFR-overexpressing gastric cancer cells (MKN-28). Nontargeted DOCT-γ-PGA Nps (NT Nps: 110±40 nm) and targeted CET MAb-DOCT-γ-PGA Nps (T Nps: 200±20 nm) were prepared using ionic gelation followed by 1-Ethyl-3-(3-dimethyl aminopropyl)carbodiimide-N-Hydoxysuccinimide (EDC-NSH) chemistry...
2017: International Journal of Nanomedicine
Doreen Könning, Laura Rhiel, Martin Empting, Julius Grzeschik, Carolin Sellmann, Christian Schröter, Stefan Zielonka, Stephan Dickgießer, Thomas Pirzer, Desislava Yanakieva, Stefan Becker, Harald Kolmar
Anti-idiotypic binders which specifically recognize the variable region of monoclonal antibodies have proven to be robust tools for pharmacokinetic studies of antibody therapeutics and for the development of cancer vaccines. In the present investigation, we focused on the identification of anti-idiotypic, shark-derived IgNAR antibody variable domains (vNARs) targeting the therapeutic antibodies matuzumab and cetuximab for the purpose of developing specific capturing ligands. Using yeast surface display and semi-synthetic, CDR3-randomized libraries, we identified several highly specific binders targeting both therapeutic antibodies in their corresponding variable region, without applying any counter selections during screening...
August 29, 2017: Scientific Reports
L Faugeras, A Dili, A Druez, B Krug, C Decoster, L D'Hondt
BACKGROUND: The survival of colorectal cancer patients is frequently determined by the extent of metastatic invasion to the liver; in cases of major involvement, therapeutic strategies are limited because the liver is necessary for drug metabolism. MATERIAL AND METHODS: We have reviewed articles about the pharmacokinetic profiles of each drug used in colorectal cancer patients with hepatic dysfunction to determine which of these treatments are most feasible. RESULTS: Some drugs appear to be feasible options for patients with hepatic insufficiency...
July 2017: Critical Reviews in Oncology/hematology
François Becher, Joseph Ciccolini, Diane-Charlotte Imbs, Clémence Marin, Claire Fournel, Charlotte Dupuis, Nicolas Fakhry, Bertrand Pourroy, Aurélie Ghettas, Alain Pruvost, Christophe Junot, Florence Duffaud, Bruno Lacarelle, Sebastien Salas
Administration of first-in-class anti-EGFR monoclonal antibody cetuximab is contingent upon extensive pharmacogenomic testing. However in addition to tumor genomics, drug exposure levels could play a critical, yet largely underestimated role, because several reports have demonstrated that cetuximab pharmacokinetic parameters, in particular clearance values, were associated with survival in patients. Here, we have developed an original bioanalytical method based upon the use of LC-MS/MS technology and a simplified sample preparation procedure to assay cetuximab in plasma samples from patients, thus meeting the requirements of standard Therapeutic Drug Monitoring in routine clinical practice...
June 2, 2017: Scientific Reports
Michèle Boisdron-Celle, Jean Philippe Metges, Olivier Capitain, Antoine Adenis, Jean Luc Raoul, Thierry Lecomte, You Heng Lam, Roger Faroux, Claude Masliah, Anne Lise Poirier, Virginie Berger, Alain Morel, Erick Gamelin
We conducted a multicenter proof of concept phase II trial in patients with advanced colorectal cancer receiving FOLFIRI-cetuximab regimens to explore individual drug tailoring using pharmacogenetics and pharmacokinetics (PK) monitoring. Patients were stratified by their pharmacogenetic/phenotypic status: the irinotecan dose was adjusted according to the number of TA tandem repeats in the UGT1A1 promoter, while the 5-fluorouracil (5-FU) dose was initially adjusted according to dihydropyrimidine dehydrogenase (DPD) activity at initial screening (5-FU(ODPM Tox)) followed by PK-guided dose optimization (5-FU(ODPM Protocol))...
February 2017: Seminars in Oncology
M Thomas, P Sadjadian, J Kollmeier, J Lowe, P Mattson, J R Trout, M Gargano, M L Patchen, R Walsh, M Beliveau, J F Marier, N Bose, K Gorden, F Schneller
Introduction BTH1677, a 1,3-1,6 beta-glucan immunomodulator, stimulates a coordinated anti-cancer immune response in combination with anti-tumor antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with cetuximab/carboplatin/paclitaxel in untreated stage IIIB/IV non-small cell lung cancer (NSCLC) patients. Methods Patients were randomized 2:1 to the BTH1677 arm (N=60; BTH1677, 4 mg/kg, weekly; cetuximab, initial dose 400 mg/m2 and subsequent doses 250 mg/m2 , weekly; carboplatin, 6 mg/mL/min AUC (area-under-the-curve) by Calvert formula, once each 3-week cycle [Q3W]); and paclitaxel, 200 mg/m2 , Q3W) or Control arm (N=30; cetuximab/carboplatin/paclitaxel as above)...
June 2017: Investigational New Drugs
James M Cleary, Autumn J McRee, Geoffrey I Shapiro, Sara M Tolaney, Bert H O'Neil, Jeffrey D Kearns, Sara Mathews, Rachel Nering, Gavin MacBeath, Akos Czibere, Sunil Sharma, W Michael Korn
Background HER3/EGFR heterodimers have been implicated as a mode of resistance to EGFR-directed therapies. Methods This Phase 1 trial assessed the tolerability, maximum tolerated dose (MTD) and pharmacokinetic (PK) properties of the HER-3 antibody seribantumab in combination with cetuximab (Part I) or cetuximab and irinotecan (Part II) in patients with EGFR-dependent cancers. In Part I, escalating doses of seribantumab and cetuximab were administered. In Part II of the trial, escalating doses of seribantumab/cetuximab were combined with irinotecan 180 mg/m2 administered every two weeks...
February 2017: Investigational New Drugs
Yoann Pointreau, Nicolas Azzopardi, David Ternant, Gilles Calais, Gilles Paintaud
BACKGROUND: A retrospective study was conducted to analyze interindividual variability of cetuximab pharmacokinetics and its influence on survival (Progression Free Survival - PFS and overall survival - OS) in a cohort of head and neck squamous cell carcinoma (HNSCC). METHODS: Thirty-four patients received cetuximab as an infusion loading dose of 400 mg/m followed by weekly infusions of 250 mg/m. Twenty-one patients had locally advanced HNSCC (LAHNSCC) and thirteen had metastatic/recurrent HNSCC (MHNSCC)...
July 4, 2016: Therapeutic Drug Monitoring
Wan-Su Park, Seunghoon Han, Jongtae Lee, Taegon Hong, Jonghwa Won, Yangmi Lim, Kyuhyun Lee, Han Yeul Byun, Dong-Seok Yim
GC1118 is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody that is currently under clinical development. In this study, the pharmacokinetics (PK) of GC1118 were modelled in monkeys to predict human PK and receptor occupancy (RO) profiles. The serum concentrations of GC1118 and its comparator (cetuximab) were assessed in monkeys with a non-compartmental analysis and a target-mediated drug disposition (TMDD) model after intravenous infusion (3-25 mg/kg) of these drugs. The scaling exponent of the EGFR synthesis rate was determined using a sensitivity analysis...
March 2017: Basic & Clinical Pharmacology & Toxicology
Yoann Pointreau, Nicolas Azzopardi, David Ternant, Gilles Calais, Gilles Paintaud
BACKGROUND: A retrospective study was conducted to analyze interindividual variability of cetuximab pharmacokinetics and its influence on survival (progression-free survival and overall survival [OS]) in a cohort of head and neck squamous cell carcinoma (HNSCC). METHODS: Thirty-four patients received cetuximab as an infusion loading dose of 400 mg/m followed by weekly infusions of 250 mg/m. Twenty-one patients had locally advanced HNSCC, and 13 had metastatic/recurrent HNSCC...
October 2016: Therapeutic Drug Monitoring
Veronika Rachar, Martin Czejka, Marie Kitzmueller, Philipp Buchner, Maria Lichtneckert, Richard Greil, Herbert Geiler, Christian Dittrich
AIM: This study focuses on the plasma disposition and metabolic activation of capecitabine (CCB) when administered alone or when combined with cetuximab (CTX). PATIENTS AND METHODS: Twenty-four chemo-naïve patients with KRAS wild-type colorectal cancer were randomized into two arms and received either CCB alone (1,000 mg/m(2) bid p.o.), followed by CCB plus CTX (loading dose (LD)=400 mg/m(2) followed by 250 mg/m(2) weekly i.v. maintenance dose) (Arm A; n=12 patients (patients)) or CCB plus CTX followed by CCB alone (Arm B; n=12 patients)...
2016: Anticancer Research
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