A5036215778- Pharmacogenetics and Drug Metabolism
- Drug Transport and Resistance Mechanisms
- Virus-based gene therapy research
- Drug-Induced Hepatotoxicity and Protection
- Hepatitis C virus research
- RNA Interference and Gene Delivery
- Pharmacological Effects and Toxicity Studies
- Liver physiology and pathology
- HIV/AIDS drug development and treatment
- Hepatitis B Virus Studies
- Liver Disease Diagnosis and Treatment
- CRISPR and Genetic Engineering
- Antibiotics Pharmacokinetics and Efficacy
- Computational Drug Discovery Methods
- Chronic Lymphocytic Leukemia Research
- Drug Solubulity and Delivery Systems
- Lipoproteins and Cardiovascular Health
- Inflammatory mediators and NSAID effects
- Cholesterol and Lipid Metabolism
- Helicobacter pylori-related gastroenterology studies
- Cancer, Lipids, and Metabolism
- Statistical Methods in Clinical Trials
- Viral Infectious Diseases and Gene Expression in Insects
- Peroxisome Proliferator-Activated Receptors
- Gut microbiota and health
Janssen (Belgium)
2016-2025
Johnson & Johnson (United States)
2008-2025
Johnson & Johnson (Israel)
2025
PharmacoGenetics (China)
2025
Janssen (United States)
2016-2023
University of Minnesota
2020
KU Leuven
2004-2018
Research Network (United States)
2016
Johnson & Johnson (Brazil)
2008
VIB-KU Leuven Center for Cancer Biology
2007
Abstract Liver biology and function, drug-induced liver injury (DILI) diseases are difficult to study using current in vitro models such as primary human hepatocyte (PHH) monolayer cultures, their rapid de-differentiation restricts usefulness substantially. Thus, we have developed extensively characterized an easily scalable 3D PHH spheroid system chemically-defined, serum-free conditions. Using whole proteome analyses, found that spheroids cultured this way were similar the vivo even...
Human embryonic stem cells (hESCs) are a valuable source of pluripotential primary cells. To date, however, their homogeneous cellular differentiation to specific cell types in vitro has proven difficult. Wnt signaling been shown play important roles coordinating development, and we demonstrate that Wnt3a is differentially expressed at critical stages human liver development vivo. The essential role hepatocyte from hESCs paralleled by our model, demonstrating the importance physiologic...
Primary human hepatocytes (PHHs) are commonly used for in vitro studies of drug-induced liver injury. However, when cultured as 2D monolayers, PHH lose crucial hepatic functions within hours. This dedifferentiation can be ameliorated PHHs sandwich configuration (2Dsw), particularly cultures regularly re-overlaid with extracellular matrix, or 3D spheroids. In this study, the 6 participating laboratories evaluated robustness these 2 model systems made from cryopreserved same donors considering...
Drug-induced mitochondrial dysfunction has been hypothesized to be an important determining factor in the onset of drug-induced liver injury. It is essential develop robust screens with which identify toxicity and dissect its role hepatotoxicity. In this study we have characterised a mechanistically refined HepG2 model, using panel selected hepatotoxicants non-hepatotoxicants. We demonstrated that acute metabolic modification, via glucose-deprivation over 4 h period immediately prior...
Abstract Predicting drug-induced liver injury in a preclinical setting remains challenging, as cultured primary human hepatocytes (PHHs), pluripotent stem cell-derived hepatocyte-like cells (HLCs), and hepatoma exhibit poor drug biotransformation capacity. We here demonstrate that hepatic functionality depends more on cellular metabolism extracellular nutrients than developmental regulators. Specifically, we increasing amino acids beyond the nutritional need of HLCs HepG2 induces glucose...
This white paper examines recent progress, applications, and challenges in predicting unbound total tissue intra/subcellular drug concentrations using vitro preclinical models, imaging techniques, physiologically based pharmacokinetic (PBPK) modeling. Published examples, regulatory submissions, case studies illustrate the application of different types data development to support modeling decision making for compounds with transporter-mediated disposition, likely disconnects between systemic...
Based on ibrutinib pharmacokinetics and potential sensitivity towards CYP3A4‐mediated drug–drug interactions (DDIs), a physiologically based pharmacokinetic approach was developed to mechanistically describe DDI with various CYP3A4 perpetrators in healthy men under fasting conditions. These models were verified using clinical data for ketoconazole (strong inhibitor) used prospectively predict confirm the inducing effect of rifampin inducer); DDIs mild (fluvoxamine, azithromycin) moderate...
The predictive performance of physiologically‐based pharmacokinetics (PBPK) models for (PK) in renal impairment (RI) and hepatic (HI) populations was evaluated using clinical data from 29 compounds with 106 organ study arms were collected 19 member companies the International Consortium Innovation Quality Pharmaceutical Development. Fifty RI 56 HI varying degrees insufficiency along control evaluated. For RI, area under curve (AUC) ratios to healthy predicted within twofold observed > 90%...
The oral bioavailability of paclitaxel is limited due to low solubility and high affinity for the P-glycoprotein (P-gp) efflux transporter. Here we hypothesized that maximizing intestinal levels through apparent enhancement controlling simultaneous release both P-gp inhibitor encequidar from amorphous solid dispersions (ASDs) would increase paclitaxel. ASDs in polyvinylpyrrolidone K30 (PVP-K30), hydroxypropylmethylcellulose 5 (HPMC-5), 4 K (HPMC-4K) were hence prepared by freeze-drying. In...
Nine static models (seven basic and two mechanistic) their respective cutoff values used for predicting cytochrome P450 3A (CYP3A) inhibition, as recommended by the US Food Drug Administration European Medicines Agency, were evaluated using data from 119 clinical studies with orally administered midazolam a substrate. Positive predictive error (PPE) negative (NPE) rates to assess model performance, based on of 1.25-fold change in area under curve (AUC) inhibitor. For reversible total or...
Abstract Ibrutinib ( PCI ‐32765), a potent covalent inhibitor of Bruton's tyrosine kinase, has shown efficacy against variety B‐cell malignancies. Given the prominent role CYP 3A in ibrutinib metabolism, effect coadministration perpetrators with was evaluated healthy adults. (120 mg [Study 1, fasted], 560 [studies 2 (fasted), and 3 (nonfasted)]) given alone ketoconazole 1; 400 q.d.], rifampin 2; 600 grapefruit juice [ GFJ , Study 3]. Lower doses were used together inhibitors 1: 40 mg; 3: 140...
TAK-875, a GPR40 agonist, was withdrawn from Phase III clinical trials due to drug-induced liver injury (DILI). Mechanistic studies were conducted identify potential DILI hazards (covalent binding burden (CVB), hepatic transporter inhibition, mitochondrial toxicity, and toxicity in rats) associated with TAK-875. Treatment of hepatocytes radiolabeled TAK-875 resulted CVB 2.0 mg/day, which is above the threshold 1 mg/day considered be risk for DILI. Covalent formation reactive acyl glucuronide...
ABSTRACT Purpose A case example is presented in which the physiologically based modeling approach has been used to model absorption of a lipophilic BCS Class II compound predominantly metabolized by CYP3A4, and assess interplay related parameters with drug–drug interaction (DDI) potential. Methods The PBPK was built rat using Gastroplus® study characteristics compound. Subsequently relevant were predict non‐linear human PK observed during first‐in‐human after optimizing for colonic...
Aims Ibrutinib, an inhibitor of Bruton's tyrosine kinase, is used in the treatment mantle cell lymphoma or chronic lymphocytic leukaemia. Ibrutinib undergoes extensive rapid oxidative metabolism mediated by cytochrome P450 3A both at level first pass and clearance, which might result low oral bioavailability. The present study was designed to investigate absolute bioavailability (F) ibrutinib fasting fed state assess effect grapefruit juice (GFJ) on systemic exposure order determine fraction...
Drug-induced liver injury (DILI), believed to be a multifactorial toxicity, has been leading cause of attrition small molecules during discovery, clinical development, and postmarketing. Identification DILI risk early reduces the costs cycle times associated with drug development. In recent years, several groups have reported predictive models that use physicochemical properties or in vitro vivo assay endpoints; however, these approaches not accounted for liver-expressed proteins molecules....
Transplant arteriosclerosis is the leading cause of graft failure and death in patients with heart transplantation. Endothelial progenitor cells (EPCs) contribute to endothelial regeneration allografts. We investigated whether increased HDL cholesterol induced by adenoviral human apoA-I (AdA-I) transfer increases number function EPCs, promotes incorporation EPCs Balb/c allografts transplanted paratopically C57BL/6 ApoE-/- mice, attenuates transplant arteriosclerosis.EPC mice was after AdA-I...
The detection of drug-induced hepatotoxicity remains an important safety issue in drug development. A liver-specific microRNA species, microRNA-122 (miR-122), has recently shown potential for predicting liver injury addition to the standard hepatic biomarkers. objective this study was measure miR-122 together with several other markers distinct settings acute toxicity rats determine value as a biomarker species. Rats were exposed 3 well-established toxicants (acetaminophen, allyl alcohol,...