A5086122369- Lipoproteins and Cardiovascular Health
- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- Cardiac electrophysiology and arrhythmias
- Systemic Lupus Erythematosus Research
- PI3K/AKT/mTOR signaling in cancer
- HIV-related health complications and treatments
- Computational Drug Discovery Methods
- Hemoglobinopathies and Related Disorders
- Pharmacological Effects and Toxicity Studies
- Gout, Hyperuricemia, Uric Acid
- Lung Cancer Treatments and Mutations
- Atherosclerosis and Cardiovascular Diseases
- PARP inhibition in cancer therapy
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Systems, Economic Evaluations, Quality of Life
- Pharmacogenetics and Drug Metabolism
- Pancreatic function and diabetes
- Diabetes Treatment and Management
- Statistical Methods in Clinical Trials
- HIV/AIDS Research and Interventions
- Heavy Metal Exposure and Toxicity
- Alcohol Consumption and Health Effects
- Erythropoietin and Anemia Treatment
- Coenzyme Q10 studies and effects
AstraZeneca (Sweden)
2017-2024
Alexion Pharmaceuticals (United States)
2024
AstraZeneca (United States)
2024
Jacksonville Center for Clinical Research
2022
AstraZeneca (Netherlands)
2021
Center for Drug Evaluation and Research
2016-2020
United States Food and Drug Administration
2016-2020
University of Gothenburg
2010-2013
University at Buffalo, State University of New York
2008
Exploration of FVC as it relates to mortality in idiopathic pulmonary fibrosis (IPF), a chronic, progressive, and ultimately fatal parenchymal lung disease, is important both clinically the current drug development paradigm. We evaluated association between decline what our knowledge largest well-characterized placebo cohort date. Additionally, we sought explore risk death caused by acute exacerbations further validate previously identified baseline predictors mortality.To characterize...
Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment dyslipidemia. Current PCSK9 inhibitors administered via subcutaneous injection. We present a highly potent, chemically modified antisense oligonucleotide (ASO) with potential oral delivery. Past attempts at delivery using earlier-generation ASO chemistries transient permeation enhancers provided encouraging data, suggesting that improving potency the...
This study aimed to test whether a pharmacokinetic simulation model could extrapolate nonclinical drug data predict human efavirenz exposure after single and continuous dosing as well the effects of concomitant rifampicin further evaluate weight-based dosage recommendations used counteract rifampicin-efavirenz interaction.Efavirenz pharmacokinetics were simulated using physiologically based implemented in Simcyp™ population-based simulator. Physicochemical metabolism obtained from literature...
The preservative thimerosal contains ethyl mercury (EtHg). Concerns over possible toxicity have re-emerged recently due to its presence in (swine and other) flu vaccines. We examined the potential accumulation of adults given repeated injections a thimerosal-preserved vaccine for many years. Fifteen female patients were recruited from an outpatient clinic running clinical trial with (1 ml every 3–4 weeks) staphylococcus toxoid containing 0.01% treat chronic fatigue syndrome. untreated same...
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...
AZD8233 is a proprotein convertase subtilisin/kexin type 9 (PCSK9) antisense oligonucleotide under development for treatment of hypercholesterolaemia. A prespecified concentration-QT analysis was performed based on data from single ascending dose study that prospectively designed to act as TQT substitute.Subcutaneous doses ranging 4 120 mg were evaluated in 73 adult healthy male subjects. Time-matched 12-lead digital ECG and plasma concentrations (n = 15) measured at baseline up 48 hours...
Abstract The International Conference on Harmonisation (ICH) E14 guidance provides recommendations to assess the potential of a drug delay cardiac repolarization (QT prolongation), including general guidelines for cases in which conventional thorough QT study (TQT) might not be feasible. These have been updated through ICH question‐and‐answer process, with last revision 2015. We conducted comprehensive analysis prolongation evaluation small‐molecule new applications (NDAs) approved oncology...
Mitiperstat is a myeloperoxidase inhibitor in clinical development for treatment of patients with heart failure and preserved or mildly reduced ejection fraction, non-alcoholic steatohepatits chronic obstructive pulmonary disease. We aimed to assess the risk QT-interval prolongation mitiperstat using concentration-QT (C-QT) modeling. Healthy male volunteers were randomized receive single oral doses 5, 15, 45, 135, 405 mg (n = 6 per dose) matching placebo 10) phase 1 study (NCT02712372)....
Dapagliflozin improves glycemic control in patients with type 2 diabetes mellitus (T2DM) and is approved Japanese 1 (T1DM) inadequate control. The objectives of this work were to characterize the dapagliflozin pharmacokinetics (PK) T1DM, assess influence covariates on PK, compare systemic exposure between T1DM T2DM. Population PK analysis was performed using a nonlinear mixed-effect modeling approach. included 5793 plasma concentrations from 1150 adult (global population), who routine...
Objective To evaluate if previously found associations between low serum bilirubin concentration and kidney function decline is independent of hemoglobin other key confounders. Research design methods Clinical trial data from the SAVOR-TIMI 53 as well UK primary care electronic healthcare records, Practice Datalink (CPRD), were used to construct three cohorts patients at risk chronic disease (CKD). The randomized clinical (RCT) cohort subset consisted 10,555 type-2 diabetic with increased...
Here, we show model-informed drug development (MIDD) of a novel antisense oligonucleotide, targeting PCSK9 for treatment hypocholesteremia. The case study exemplifies use MIDD to analyze emerging data from an ongoing first-in-human study, utility the US Food and Drug Administration pilot program accelerate timelines, innovative competitor set biomarker targets, optimize sample size dose selection, as well de-risk phase IIb study. focus case-study is on cross-functional collaboration other...
Verinurad, a uric acid transporter 1 (URAT1) inhibitor, lowers serum by promoting its urinary excretion. Co-administration with xanthine oxidase inhibitor (XOI) to simultaneously reduce production rate reduces the potential for renal tubular precipitation of acid, which can lead acute kidney injury. The combination is currently in development chronic disease and heart failure. aim this work was apply extend previously developed semi-mechanistic exposure-response model kinetics include...
Pharmacokinetics-matched digital electrocardiogram data (n = 503 measurements from 180 patients) collected in a first-in-human, multi-part, dose-escalation (from 80 to 800 mg) and dose expansion (at 480 phase 1 study patients with advanced solid malignancies, were used assess potential risk of QT prolongation associated the AKT inhibitor capivasertib. The relationship between plasma drug concentrations baseline-adjusted Fridericia-corrected (ΔQTcF) values was estimated using prespecified...
Concentration-QT modelling (C-QTc) of first-in-human data has been rapidly adopted as the primary evaluation QTc interval prolongation risk. Here, we evaluate performance C-QTc in early oncology settings (i.e., patients, no placebo or supratherapeutic dose, 3 + designs).C-QTc was evaluated across three scenarios using a simulation-estimation approach: (scen1) typical dose-escalation testing six dose levels (n = 21); (scen2) small two 9); (scen3) expansion cohorts at one level 6-140). True...
Current PCSK9 inhibitors are administered via subcutaneous (SC) injection. Here, we present a highly potent, chemically modified antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at delivery using earlier ASO chemistries and intestinal permeation enhancers provided encouraging data, suggesting that improving potency of the could make reality. The constrained ethyl chemistry liver targeting enabled by tri-antennary N -acetyl galactosamine (GalNAc) conjugation...