A5044081105- Lung Cancer Treatments and Mutations
- HER2/EGFR in Cancer Research
- Drug Transport and Resistance Mechanisms
- Pharmacological Effects and Toxicity Studies
- Hepatocellular Carcinoma Treatment and Prognosis
- Pharmacogenetics and Drug Metabolism
- Colorectal Cancer Treatments and Studies
- Cancer, Hypoxia, and Metabolism
- Angiogenesis and VEGF in Cancer
- Cancer Treatment and Pharmacology
- Peptidase Inhibition and Analysis
- Renal cell carcinoma treatment
- Antibiotics Pharmacokinetics and Efficacy
- Chronic Lymphocytic Leukemia Research
- Chronic Myeloid Leukemia Treatments
- Medical Imaging Techniques and Applications
- Computational Drug Discovery Methods
- Pancreatic and Hepatic Oncology Research
- Ovarian cancer diagnosis and treatment
- Prostate Cancer Treatment and Research
- Microscopic Colitis
- Radiopharmaceutical Chemistry and Applications
- Asthma and respiratory diseases
- Cancer therapeutics and mechanisms
- Gastric Cancer Management and Outcomes
Boehringer Ingelheim (Germany)
2015-2025
University of Florida
2016
Columbus Oncology and Hematology Associates
2016
Reckitt Benckiser (United States)
2016
Boehringer Ingelheim (Australia)
2014
Boehringer Ingelheim (United States)
2006-2010
Indiana University – Purdue University Indianapolis
2010
Indiana University School of Medicine
2010
Boehringer Ingelheim (Canada)
2010
Wellcome Sanger Institute
2010
Preclinical data have demonstrated that BIBW 2992 is a potent irreversible inhibitor of ErbB1 (EGFR/HER1) and mutated receptors including the T790M variant, as well ErbB2 (HER2). A phase I study continuous once-daily oral was conducted to determine safety, maximum-tolerated dose, pharmacokinetics (PK), food effect, preliminary antitumor efficacy.Patients with advanced solid tumors were treated. PK evaluation performed after first dose at steady-state.Fifty-three patients received 10 50 mg/d....
To assess tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of the dual epidermal growth factor receptor (EGFR) 1 2 (HER2) tyrosine kinase inhibitor BIBW 2992. An escalating schedule once-daily (OD) 2992 for 14 days followed by off medication was explored. Thirty-eight patients were enrolled. Dose levels 10, 20, 30, 45, 70, 85, 100 mg. At mg dose-limiting toxicity (DLT) (common criteria grade 3 skin rash diarrhoea despite treatment with loperamide) occurred in...
BIBF 1120 is an oral, potent angiokinase inhibitor targeting receptors of the vascular endothelial growth factors, platelet-derived and fibroblast factors. This phase I, accelerated titration study assessed maximum tolerated dose, safety, pharmacokinetics, pharmacodynamic effects 1120.Sixty-one patients with advanced cancers received in successive cohorts. Twenty-five 50 to 450 mg once daily 36 150 300 twice 4-week treatment courses interspersed by 1 week washout. Dynamic contrast-enhanced...
Physiologically based pharmacokinetic (PBPK) models are increasingly used to predict food effect (FE) but model parameterization is challenged by in vitro-in vivo (IVIV) disconnect and/or parameter nonidentifiability. To overcome these issues, we propose a simplified PBPK model, which all solubility-driven processes lumped into single parameter, solubility, optimized against observed concentration-time data. A set of commercially available biopharmaceutical classification system (BCS) II/IV...
BIBF 1120 (planned brand name Vargatef) is a novel, oral, triple angiokinase inhibitor targeting three receptor classes involved in blood vessel formation. The objectives of this phase I, open-label dose-escalation study were to determine the safety, tolerability, and maximum tolerated dose (MTD) with pemetrexed patients recurrent advanced-stage non-small cell lung carcinoma.Patients harboring tumor any carcinoma histology, previously treated one first-line platinum-based chemotherapy...
This article reports the clinical investigation of a probe drug cocktail containing substrates key transporters. Single oral doses 0.25 mg digoxin (P‐gp), 5 furosemide (OAT1 and OAT3), 500 metformin (OCT2, MATE1, MATE2‐K), 10 rosuvastatin (OATP1B1, OATP1B3, BCRP) were administered separately or as in randomized six‐period crossover trial 24 healthy male volunteers. As cocktail, relative bioavailabilities AUC 0‐tz similar to separate dosing. However, when C max was 19.1% lower 38.6% 43.4%...
The pharmacokinetics and metabolism of BIBF 1120, an oral triple angiokinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived (PDGFR), fibroblast (FGFR), were studied in healthy male volunteers (n = 8) who had received a single dose 100 mg [14C]-radiolabelled 1120 administered as solution.BIBF was well-tolerated rapidly absorbed; median time to reach maximum plasma concentrations 1.3 h gMean terminal half-life 13.7 h. A relatively high apparent total...
A novel cocktail containing four substrates of key drug transporters was previously optimized to eliminate mutual drug–drug interactions between the probes digoxin (P-glycoprotein substrate), furosemide (organic anion transporter 1/3), metformin cation 2, multidrug and toxin extrusion protein 1/2-K), rosuvastatin transporting polypeptide 1B1/3, breast cancer resistance protein). This clinical trial investigated effects commonly employed inhibitors on pharmacokinetics. In a randomized...
Metformin is a widely prescribed antidiabetic BCS Class III drug (low permeability) that depends on active transport for its absorption and disposition. It recommended by the US Food Drug Administration as clinical substrate of organic cation transporter 2/multidrug toxin extrusion protein drug–drug interaction studies. Cimetidine potent inhibitor. The objective this study was to provide mechanistic whole-body physiologically based pharmacokinetic models metformin cimetidine, built evaluated...
N 1 ‐methylnicotinamide (NMN) has been proposed as endogenous biomarker for drug–drug interactions mediated by inhibition of multidrug and toxin extrusion proteins (MATEs) at the renal proximal tubule. We analyzed NMN in plasma urine samples two clinical trials investigating a new probe drug cocktail (consisting digoxin, metformin, furosemide, rosuvastatin) dedicated to clinically relevant transporters. In trial 1, was investigated after single‐dose treatment with individual components or...
Endogenous biomarkers are discussed as tools for detection of drug‐drug interactions (DDIs) mediated by renal transport proteins, such organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATE1 MATE2‐K) anion transporters (OAT1 OAT3). Whereas sensitivity some endogenous against at least one clinical inhibitor has frequently been shown, intra‐study comparisons the extent effects inhibitors on different lacking. Moreover, in vivo specificity not studied. We therefore...
Background: Pharmacokinetic drug–drug interactions (DDIs) can be caused by the effect of a pharmaceutical compound on activity one or more subtypes Cytochrome P450 (CYP) family, UDP-glucuronosyltransferases (UGTs), and/or transporters. As number therapeutic areas with polypharmacy has increased, interest grown in assessing risk DDIs during early phases drug development. Various lines research have led to improved mathematical models predict DDIs, culminating Food and Drug Administration’s...
Abstract Nintedanib, a triple angiokinase inhibitor, has undergone clinical investigation for the treatment of solid tumors and idiopathic pulmonary fibrosis. Nintedanib (Vargatef ® ) plus docetaxel is approved in EU patients with adenocarcinoma non‐small cell lung cancer (NSCLC) after first‐line chemotherapy, as monotherapy (Ofev United States Pharmacokinetics (PK) nintedanib oral single multiple doses intravenous (IV) administration were assessed using 3 data sets: (1) an absolute...
Aims Previous pharmacokinetic characterization of a transporter probe cocktail containing digoxin (P‐gp), furosemide (OAT1, OAT3), metformin (OCT2, MATE1, MATE2‐K) and rosuvastatin (OATP1B1, OATP1B3, BCRP) in healthy subjects showed increases systemic exposure compared to alone. In this trial, the doses as putative perpetrators were reduced eliminate their drug–drug interaction (DDI) with rosuvastatin. Methods randomized, open‐label, single‐centre, five‐treatment, five‐period crossover 30...
Abstract Lymphotoxin-β receptor (LTβR) signaling is known to play a key role in embryonic lymphoid organ formation as well maintenance of architecture. Activation the LTβR induced by either heterotrimeric lymphotoxin-α1β2 (LTα1β2) or homotrimeric LIGHT (homologous lymphotoxins, exhibits inducible expression, and competes with HSV gpD for herpes virus entry mediator, expressed T lymphocyte). Both ligands are on activated lymphocytes. As mast cells reside close proximity some inflammatory...
Summary Background A Phase I study to determine the maximum tolerated dose (MTD) and pharmacokinetics of afatinib (BIBW 2992), a novel irreversible ErbB Family Blocker, administered orally once daily in 3-week-on/1-week-off dosing schedule. Methods Patients with advanced solid tumors received single-agent at 10, 20, 40, 55 or 65 mg/day. Safety, antitumor activity, pharmacodynamic modulation biomarkers were assessed. Results : Forty-three patients enrolled. Dose-limiting toxicities (DLTs)...