Cetuximab pharmacokinetics

BACKGROUND AND OBJECTIVES: Encorafenib is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma or metastatic colorectal cancer, respectively, with selected BRAF V600 mutations. A clinical drug-drug interaction (DDI) study was designed to evaluate the effect of encorafenib on rosuvastatin, a sensitive substrate of OATP1B1/3 and breast cancer resistance protein (BCRP), and bupropion, a sensitive CYP2B6 substrate. Coproporphyrin I (CP-I), an endogenous substrate for OATP1B1, was measured in a separate study to deconvolute the mechanism of transporter DDI...

Afatinib (AT), an FDA-approved aniline-quinazoline derivative, is a first-line treatment for metastatic non-small cell lung cancer (NSCLC). Combining it with cetuximab (CX), a chimeric human-murine derivative immunoglobulin-G1 monoclonal antibody (mAb) targeting the extracellular domain of epidermal growth factor receptor (EGFR), has shown significant improvements in median progression-free survival. Previously, we developed cetuximab-conjugated immunoliposomes loaded with afatinib (AT-MLP) and demonstrated their efficacy against NSCLC cells (A549 and H1975)...

Natural killer (NK) cells emerged as a promising effector population that can be harnessed for anti-tumor therapy. In this work, we constructed NK cell engagers (NKCEs) based on NKp30-targeting single domain antibodies (sdAbs) that redirect the cytotoxic potential of NK cells toward epidermal growth factor receptor (EGFR)-expressing tumor cells. We investigated the impact of crucial parameters such as sdAb location, binding valencies, the targeted epitope on NKp30, and the overall antibody architecture on the redirection capacity...

BACKGROUND: Mutations in the epidermal growth factor receptor (EGFR) kinase domain are common in non-small cell lung cancer. Conventional tyrosine kinase inhibitors target the mutation site in the ATP binding pocket, thereby inhibiting the receptor's function. However, subsequent treatment resistance mutations in the ATP binding site are common. The EGFR allosteric inhibitor, EAI045, is proposed to have an alternative mechanism of action, disrupting receptor signaling independent of the ATP-binding site...

Cetuximab resistance is a significant challenge in cancer treatment, requiring the development of novel therapeutic strategies. In this study, a series of multivalent rhamnose (Rha)-modified nanobody conjugates are synthesized and their antitumor activities and their potential to overcome cetuximab resistance are investigated. Structure-activity relationship studies reveal that the multivalent conjugate D5, bearing sixteen Rha haptens, elicits the most potent innate fragment crystallizable (Fc) effector immunity in vitro and exhibits an excellent in vivo pharmacokinetics by recruiting endogenous antibodies...

Antibody-drug conjugates (ADCs) make up a growing class of targeted therapeutics with important applications in cancer treatment. ADCs are highly modular in nature and thus can be engineered to target any cancer type, but their efficacy is strongly influenced by the specific choice of payload, antibody, and target cell. Considering the number of possible antibody-payload combinations, ADC development would benefit from an efficient method to narrow the number of ADC compositions to those with the highest and most universal potency prior to assessing pharmacokinetics and pharmacodynamics in animal models...

Cetuximab every 2 weeks (Q2W) dosing schedule is approved by the US FDA and by the Japanese Pharmaceuticals and Medical Devices Agency in patients with metastatic colorectal cancer and squamous cell carcinoma of the head and neck. Phase II trials have found comparable efficacy and safety for the weekly (Q1W) and Q2W schedules, and real-world studies have shown noninferiority of the Q2W compared with the Q1W schedule. Several guidelines recommend cetuximab Q2W administration as an alternative to the Q1W dosing schedule...

Therapeutic antibodies have shown little efficacy in the treatment of pancreatic ductal adenocarcinomas (PDAC). Tumor desmoplasia, hypovascularity, and poor perfusion result in insufficient tumor cell exposure, contributing to treatment failure. Smoothened inhibitors of sonic hedgehog signaling (sHHi) increase PDAC tumor permeability, perfusion, and drug delivery, and provide a tool to develop a quantitative, mechanistic understanding as to how the temporal dynamics of tumor priming can impact intratumor distribution of antibodies (mAb)...

To be profitably exploited in medicine, nanosized systems must be endowed with biocompatibility, targeting capability, the ability to evade the immune system, and resistance to clearance. Currently, biogenic nanoparticles, such as extracellular vesicles (EVs), are intensively investigated as the platform that naturally recapitulates these highly needed characteristics. EV native targeting properties and pharmacokinetics can be further augmented by decorating the EV surface with specific target ligands as antibodies...

BACKGROUND: Cetuximab is a standard of care therapy for patients with RAS wild-type (WT) advanced colorectal cancer. Limited data suggest a wide variation in cetuximab plasma concentrations after standard dosing regimens. We correlated cetuximab plasma concentrations with survival and toxicity. METHODS: The CO. 20 study randomized patients with RAS WT advanced colorectal cancer in a 1:1 ratio to cetuximab 400 mg/m2 intravenously followed by weekly maintenance of 250 mg/m2 , plus brivanib 800 mg orally daily or placebo...

BACKGROUND AND OBJECTIVE: Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal immunoglobulin (Ig)G1 antibody, has been approved for the treatment of metastatic colorectal cancer (mCRC). The influence of target-antigen on cetuximab pharmacokinetics has never been investigated using target-mediated drug disposition (TMDD) modelling. This study aimed to investigate the relationship between cetuximab concentrations, target kinetics and progression-free survival (PFS). METHODS: In this ancillary study (NCT00559741), 91 patients with mCRC treated with cetuximab were assessed...

This study aimed to develop cetuximab (CTX) functionalized albumin nanoparticles (ALB-NPs) of oleanolic acid for EGFR targeted lung cancer therapy. The molecular docking methodology has been applied for selection of suitable nanocarrier. Various physicochemical parameters like particle size, polydispersity, zeta potential, morphology, entrapment efficiency, and in-vitro drug release of all the ALB-NPs were analyzed. Furthermore, the in-vitro qualitative and quantitative cellular uptake study revealed higher uptake of CTX targeted ALB-NPs than nontargeted ALB-NPs in A549 cells...

We evaluated the safety, tolerability, pharmacokinetics and antitumor activity of barecetamab monotherapy and combination cetuximab therapy in patients with advanced solid cancers, especially head and neck cancer (HNC). Part 1 was a 3 + 3 dose-escalation study in which 15 patients received barecetamab at 1, 3, 5, 10 and 20 mg/kg intravenously (IV) on days 1 and 28 and weekly in patients with advanced solid cancer. Part 2 was a dose-expansion study including two patient groups with advanced HNC, including six patients receiving barecetamab at 20 mg/kg IV every 3 weeks and 12 patients receiving barecetamab and cetuximab (400 mg/m2 on day 1 followed by 250 mg/m2 every week)...

AIM: To use population physiologically based pharmacokinetic (PopPBPK) modelling to optimise target expression, kinetics and clearance of HER1/2 directed therapeutic monoclonal antibodies (mAbs). Thus, to propose a general workflow of PopPBPK modelling and its application in clinical pharmacology. METHODS: Full PBPK model of pertuzumab (PTZ) was developed in patient population using Simcyp V21R1 incorporating mechanistic targeted-mediated drug disposition (TMDD) process by fitting known clinical PK and sparse receptor proteomics data to optimise target expression and kinetics of HER2 receptor...

Engineered Fab fragments of monoclonal antibodies (mAbs) after radiolabeling with suitable radiometals have the potential to play a key role in personalized radioimmunotheranostics of cancer patients. In this study, we have generated Fab fragment of Cetuximab, a mAb targeting epidermal growth factor receptor (EGFR) expression and purified from the Fc and other fragments by ultrafiltration and affinity chromatography. The Cetuximab-Fab was conjugated with a suitable bifunctional chelator and radiolabeled with no-carrier-added (NCA) 64 Cu produced via 64 Zn (n, p) 64 Cu reaction in a nuclear reactor...

INTRODUCTION: The introduction of monoclonal antibodies to the chemotherapy backbone treatment has challenged the paradigm of metastatic colorectal cancer (mCRC) treatment. Their mechanism of action and pharmacokinetics are complex but important to understand in order to improve patient selection and treatment outcomes for mCRC population. AREAS COVERED: This review examines the scientific data, pharmacodynamics, and pharmacokinetics of approved monoclonal antibodies used to treat mCRC patients, including agents targeting signaling via VEGFR (bevacizumab and ramucirumab), EGFR (cetuximab and panitumumab), HER2/3 target therapy, and immunotherapy agents such as pembrolizumab or nivolumab...

Effective processes for synthesizing antibody-drug conjugates (ADCs) require: 1) site-specific incorporation of the payload to avoid interference with binding to the target epitope, 2) optimal drug/antibody ratio to achieve sufficient potency while avoiding aggregation or solubility problems, and 3) a homogeneous product to facilitate approval by regulatory agencies. In conventional ADCs, the drug molecules are chemically attached randomly to antibody surface residues (typically Lys or Cys), which can interfere with epitope binding and targeting, and lead to overall product heterogeneity, long-term colloidal instability and unfavorable pharmacokinetics...

89 Zr represents a highly favorable positron emitter for application in immuno-PET (Positron Emission Tomography) imaging. Clinically, the 89 Zr4+ ion is introduced into antibodies by complexation with desferrioxamine B. However, producing complexes of limited kinetic inertness. Therefore, several new chelators for 89 Zr introduction have been developed over the last years. Of these, the direct comparison of the most relevant ones for clinical translation, DFO* and 3,4,3-(LI-1,2-HOPO), is still missing. Thus, we directly compared DFO with DFO* and 3,4,3-(LI-1,2-HOPO) immunoconjugates to identify the most suitable agent stable 89 Zr-complexation...

Objective: To provide a comprehensive review of intra-arterial cerebral infusions of chemotherapeutics in glioblastoma multiforme treatment and discuss potential research aims. We describe technical aspects of the intra-arterial delivery, methods of blood-brain barrier disruption, the role of intraoperative imaging and clinical trials involving intra-arterial cerebral infusions of chemotherapeutics in the treatment of glioblastoma multiforme. Method: 159 articles in English were reviewed and used as the foundation for this paper...

Canakinumab is a fully-human monoclonal immunoglobulin gamma 1 kappa. This interleukin-1β blocker is used for the treatment of autoinflammatory diseases. Various studies have demonstrated the value of therapeutic drug monitoring of monoclonal antibodies in the management of inflammatory diseases. The purpose of this study was to develop a method to quantify canakinumab plasmatic concentration using liquid chromatography-high-resolution (Orbitrap®) mass spectrometry. The quantification was based on a bottom-up approach with the analysis of one surrogate peptide after an immunopurification of IgG followed by tryptic proteolysis...