A5091201149- Alzheimer's disease research and treatments
- Monoclonal and Polyclonal Antibodies Research
- HER2/EGFR in Cancer Research
- Cholinesterase and Neurodegenerative Diseases
- Computational Drug Discovery Methods
- Peptidase Inhibition and Analysis
- Dementia and Cognitive Impairment Research
- Neutropenia and Cancer Infections
- Asthma and respiratory diseases
- Blood disorders and treatments
- Acute Lymphoblastic Leukemia research
- Breast Cancer Treatment Studies
- Chronic Lymphocytic Leukemia Research
- Cancer Treatment and Pharmacology
- Allergic Rhinitis and Sensitization
- Colorectal Cancer Treatments and Studies
- Inhalation and Respiratory Drug Delivery
- Renal Transplantation Outcomes and Treatments
- S100 Proteins and Annexins
- Acute Myeloid Leukemia Research
- Immune Response and Inflammation
- Chronic Myeloid Leukemia Treatments
- Inflammatory Biomarkers in Disease Prognosis
- Brain Tumor Detection and Classification
- Ion Channels and Receptors
AstraZeneca (Sweden)
2014-2024
AstraZeneca (United States)
2014-2021
Jacksonville Center for Clinical Research
2021
Brain Matters Research
2018
Compass Research
2018
Yale University
2018
Lou Ruvo Brain Institute
2018
Roche Pharma AG (Germany)
2018
Cleveland Clinic
2018
Uppsala University
2007-2017
To evaluate the safety and efficacy of crenezumab in patients with mild to moderate Alzheimer disease (AD).In this phase 2 trial, 431 AD 50 80 years age were randomized 2:1 (crenezumab:placebo). Patients received low-dose subcutaneous 300 mg or placebo every weeks (n = 184) high-dose intravenous 15 mg/kg 4 247) for 68 weeks. Primary outcome measures change Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) Clinical Dementia Rating-Sum Boxes scores from baseline week 73.The...
Importance Alzheimer disease (AD), a neurodegenerative characterized by β-amyloid plaques and τ tangles in the brain, represents an unmet medical need with no fully approved therapeutics to modify progression. Objective To investigate safety efficacy of crenezumab, humanized monoclonal immunoglobulin G4 antibody targeting oligomers, participants prodromal mild (early) AD. Design, Setting, Participants Two phase 3 multicenter randomized double-blind placebo-controlled parallel-group studies...
We investigated the effect of crenezumab, a humanized anti-amyloid-beta (Aβ) immunoglobulin (Ig)G4 monoclonal antibody, on biomarkers amyloid pathology, neurodegeneration, and disease progression in patients with mild-to-moderate Alzheimer's (AD). This double-blind, placebo-controlled, randomized phase II study enrolled AD Mini-Mental State Examination (MMSE) score 18–26. In part 1 study, were 2:1 to receive low-dose subcutaneous (SC) 300 mg crenezumab every 2 weeks (q2w) or placebo for 68...
To characterize the population pharmacokinetics (PKs) of subcutaneous (SC) and intravenous (IV) trastuzumab in early breast cancer (EBC), assess impact covariates on PK, evaluate fixed (nonweight-based) dosing for SC regimen administrated via handheld syringe. Serum concentrations from 595 patients with HER2-positive EBC HannaH study (fixed 600 mg or weight-based IV trastuzumab) were analyzed using nonlinear mixed-effects modeling. Multiple logistic regression was used to exposure–response...
Bevacizumab is approved for various cancers. This analysis aimed to comprehensively evaluate bevacizumab pharmacokinetics and the influence of patient variables on pharmacokinetics. Rich sparse serum concentrations were collected from Phase I through IV studies in early metastatic was given intravenously as single agent or combination with chemotherapy single- multiple-dose schedules. Model-building used 8943 1792 patients colon/colorectal, non-small cell lung, kidney, pancreatic, breast,...
Background: Crenezumab is a fully humanized, monoclonal anti-amyloid-β immunoglobulin G4 antibody. Objective: This Phase Ib study (NCT02353598) evaluated the safety, tolerability, and pharmacokinetics of crenezumabat doses ≤120 mg/kg administered intravenously every 4 weeks (q4w). Immunogenicity exploratory biomarkers were also evaluated. Methods: In this multicenter, double-blind study, participants (aged 50–90 years) with mild-to-moderate Alzheimer’s disease (AD) amyloid-positive positron...
Abstract Background Crenezumab, a fully humanized anti-beta-amyloid (Aβ) immunoglobulin G4 (IgG4) monoclonal antibody, binds to both monomeric and aggregated forms of Aβ. We assessed the pharmacokinetics (PK)/pharmacodynamics (PD) crenezumab its interaction with Aβ(1–40) Aβ(1–42) peptides in serum/plasma cerebrospinal fluid (CSF) samples from phase II ABBY BLAZE studies Ib GN29632 study. Methods In ABBY, BLAZE, studies, patients mild-to-moderate AD were treated either placebo or (300 mg...
Background Blockade of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a potentially attractive mechanism for lowering inflammatory and lipid risk in patients with atherosclerosis. This study aims to assess safety, tolerability, target engagement MEDI6570, high-affinity monoclonal blocking antibody LOX-1. Methods Results phase 1, first-in-human, placebo-controlled (NCT03654313) randomized 88 type 2 diabetes receive single ascending doses (10, 30, 90, 250, or 500 mg)...
There is strong interest in developing predictive models to better understand individual heterogeneity and disease progression Alzheimer's (AD). We have built upon previous longitudinal AD models, using a nonlinear, mixed-effect modeling approach predict Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) progression. Data from the Disease Neuroimaging Initiative (observational study) placebo arms four interventional trials (N = 1093) were used for model building. The two additional 805)...
The aim of the present study was to evaluate pharmacokinetics bevacizumab and various dosing strategies for this agent in paediatric patients.Data were collected from 232 patients (1971 concentrations) five studies, with a wide range age (0.5-21 years), body weight (BWT; 5.9-125 kg), regimens (5-15 mg kg(-1) biweekly or triweekly). Data 152 (1427 80 (544 used model building external validation, respectively. Steady-state exposure simulated under BWT-based, surface area (BSA)-based, ideal...
The aim of the study was to characterize population pharmacokinetics (PK) intravenous formulation trastuzumab, assess impact patient and pathological covariates on trastuzumab PK, perform simulations support dosing recommendations in special situations.Serum concentrations were obtained from 1582 patients with metastatic breast cancer (MBC), early (EBC), advanced gastric (AGC), or other tumor types/healthy volunteers 18 phase I, II, III trials analyzed by nonlinear mixed-effects modeling.A...
Abstract Despite considerable investment into potential therapeutic approaches for Alzheimer's disease (AD), currently approved treatment options are limited. Predictive modeling using quantitative systems pharmacology (QSP) can be used to guide the design of clinical trials in AD. This study developed a QSP model representing amyloid beta (Aβ) pathophysiology The included mechanisms Aβ monomer production and aggregation form insoluble fibrils plaques; transport soluble species between...
The NeoSphere trial evaluated pertuzumab in the neoadjuvant setting [early breast cancer (EBC)] with pathological complete response (pCR) as primary efficacy end point. This analysis of aimed to (1) compare its pharmacokinetics (PK) patients EBC versus advanced cancers, (2) further evaluate PK drug-drug interactions (DDIs) when given combination trastuzumab, and (3) assess relationship between exposure clinical dosing regimen patients.Pertuzumab serum concentration data from 180 were...
It has been shown that the cellular uptake and cytotoxicity of anthracyclines decrease with increasing cell density in vitro, an event termed 'the inocculum effect'. is not known whether such effect occurs vivo. In this study relationships between white blood (WBC) count, plasma concentrations daunorubicin (DNR) patients acute myeloid leukaemia were investigated.Plasma mononuclear cells isolated from peripheral 40 at end infusion (time 1 h), 5 24 h following first DNR infusion. determined by...
GDC-0334 is a novel small molecule inhibitor of transient receptor potential cation channel member A1 (TRPA1), promising therapeutic target for many nervous system and respiratory diseases. The pharmacokinetic (PK) profile pharmacodynamic (PD) effects were evaluated in this first-in-human (FIH) study. A starting single dose 25 mg was selected based on integrated preclinical PK, PD, toxicology data following oral administration guinea pigs, rats, dogs, monkeys. Human PK PK-PD characterized...
Compared with intravenous formulations, subcutaneous (s.c.) formulations of therapeutic monoclonal antibodies may provide increased patient access and more convenient administration options, although historically high-volume s.c. (> 10-15 mL) has been challenging. We report results from two phase I studies in healthy participants (GP29523 GP40201) that evaluated crenezumab, an anti-Aβ antibody development for individuals at risk autosomal-dominant Alzheimer's disease. GP29523 assessed...
Abstract Aims The aim of this study was to characterize the population pharmacokinetics AZD8233, an antisense oligonucleotide (ASO) that targets PCSK9 transcript reduce hepatocyte protein production and plasma levels. AZD8233 utilizes generation 2.5 S‐constrained ethyl motif (cET) chemistry is conjugated a triantennary N ‐acetylgalactosamine (GalNAc3) ligand for targeted uptake. Methods A non‐linear mixed‐effect modelling approach utilizing NONMEM software applied concentration–time data...
Abstract Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. This analysis assessed suitability fixed‐dose regimen tezepelumab 210 mg every 4 weeks (Q4W) in adults and adolescents with severe, uncontrolled asthma. A population pharmacokinetic model was developed using data from 1368 patients asthma or healthy participants enrolled 8 clinical studies (phases 1‐3). exposure‐efficacy relationships were analyzed phase 3 NAVIGATOR study...
We conducted population pharmacokinetic (PopPK) and exposure-response analyses for trastuzumab emtansine (T-DM1), to assess the need T-DM1 dose optimization in patients with low exposure by using TH3RESA [A Study of Trastuzumab Emtansine Comparison With Treatment Physician's Choice Patients human epidermal growth factor receptor 2 (HER2)-positive Breast Cancer Who Have Received at Least Two Prior Regimens HER2-directed Therapy] study data (NCT01419197). The randomized phase III investigated...
Modulating deposition of Aβ-containing plaques in the brain may be beneficial treating Alzheimer's disease. β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors have been shown to reduce Aβ plasma and CSF healthy volunteers. In this study safety, pharmacokinetics pharmacodynamics that is reduction biomarkers Aβ40 Aβ42 , BACE1 inhibitor AZD3839 were evaluated. Single oral ascending doses (1-300 mg) administered 54 young volunteers a randomized, double-blind,...
An item response theory (IRT) pharmacometric framework is presented to characterize Functional Assessment of Cancer Therapy-Breast (FACT-B) data in locally-advanced or metastatic breast cancer patients treated with ado-trastuzumab emtansine (T-DM1) capecitabine-plus-lapatinib. In the IRT model, four latent well-being variables, based on FACT-B general subscales, were used describe physical, social/family, emotional and functional well-being. Each subscale was reassigned one other subscales....