1β-Hydroxydeoxycholic acid as an endogenous biomarker in human plasma for assessment of drug-drug interaction with moderate CYP3A inhibitor.

1β-Hydroxydeoxycholic acid (1β-OH DCA) in plasma has been shown to be a promising biomarker to assess drug-drug interaction (DDI) with a strong CYP3A inducer or a strong CYP3A inhibitor. The changes in total 1β-OH DCA (sum of 1β-OH DCA, 1β-OH glycine deoxycholic acid, and 1β-OH taurine deoxycholic acid equivalents) were more significant than those observed from 4β-hydroxycholesterol, which has been limited to the identification of CYP3A inducers, not CYP3A inhibitors. The significant reduction in total 1β-OH DCA in response to strong CYP3A inhibitors led us to further explore its utility as a biomarker for DDI with moderate CYP3A inhibitors.

Pharmacokinetics, safety, and tolerability of fedratinib in adults with moderate and severe hepatic impairment: results from the phase 1 FEDR-CP-001 trial.

Purpose: The FEDR-CP-001 (NCT03983161) trial evaluated the pharmacokinetics (PK) and safety of a single dose of fedratinib in adults with moderate or severe hepatic impairment (HI) compared with matched healthy participants with normal hepatic function.

Methods: This was a non-randomized, open-label, multicenter, phase 1 trial. Participants were aged 18-75 years and had a BMI of 18-40 kg/m.

Exposure-response relationship of fedratinib in patients with intermediate-2 or high-risk myelofibrosis.

Aims: Fedratinib is a potent, oral, Janus kinase inhibitor for the treatment of myelofibrosis (MF). This report describes exposure-response (E-R) analyses of fedratinib based on pooled data from phase 2/3 studies in patients with intermediate-2 or high-risk MF, with or without prior ruxolitinib exposure.

Methods: Pharmacokinetic (PK) exposures were derived from the population PK analysis.

Evaluating the utility of endogenous OCT2 and MATE1/2-K biomarkers for DDI assessment in early clinical settings.

With growing interest in a biomarker-based approach for drug-drug interaction (DDI) predictions, creatinine, N1-methylnicotinamide (NMN), and N1-methyladenosine (mA) have been identified as endogenous substrates of organic cation transporter (OCT) 2 and multidrug and toxin extrusion (MATE) 1/2-K, though clinical validation remains limited. This study builds on recent advancements by evaluating these biomarkers retrospectively using samples from a clinical pharmacology study that assessed DDI via renal cationic transporters between fedratinib (inhibitor) and metformin (substrate) in healthy participants. Fedratinib reduced renal clearance for all endogenous substrates, with mA (38 %) and NMN (36 %) showing reductions comparable to metformin (40 %), while creatinine exhibited slightly lower (29 %), likely reflecting its limited contribution to transporter-mediated renal tubular secretion.

Identification and Clinical Evaluation of Potential Biomarkers for Breast Cancer Resistance Protein (BCRP/ABCG2).

Clinical inhibition and genetic variation of the Breast Cancer Resistance Protein (BCRP/ABCG2) efflux transporter can significantly influence drug exposure, highlighting the need for reliable BCRP functional biomarkers. This study aimed to identify and evaluate biomarkers predictive of BCRP function in humans. A comprehensive analysis of metabolomic genome-wide association studies (mGWAS) was conducted to discover potential BCRP biomarkers, followed by evaluation in in vitro transporter assays and a clinical drug-drug interaction (DDI) study.

A population pharmacokinetic analysis to evaluate the impact of renal impairment on the pharmacokinetics of iberdomide.

Iberdomide, a novel potent cereblon E3 ligase modulator, is under investigation for multiple myeloma. This study assessed how renal impairment (RI) affects iberdomide pharmacokinetics (PK). Twenty-six subjects with varying renal function, including those with severe renal impairment and those requiring intermittent hemodialysis (IHD), received a single oral 1 mg dose of iberdomide.

2024 White Paper on Recent Issues in Bioanalysis: Three Way-Cross Validation; Urine Clinical Analysis; Automated Methods; Regulatory Queries on Plasma Protein Binding; Automated Biospecimen Management; ELN Migration; Ultra-Sensitivity Mass Spectrometry ( - Recommendations on Advanced Strategies for Mass Spectrometry Assays, Chromatography, Sample Preparation and BMV/Regulated Bioanalysis - Regulatory Agencies' Inputs on Regulated Bioanalysis/BMV).

The 18 Workshop on Recent Issues in Bioanalysis (18 WRIB) took place in San Antonio, TX, USA on May 6-10, 2024. Over 1100 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 18 WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week to allow an exhaustive and thorough coverage of all major issues in bioanalysis of biomarkers, immunogenicity, gene therapy, cell therapy and vaccines.

Gradient Hierarchically Porous Ionic-Junction Fibers of Wet-Spun Carboxymethyl Cellulose Coagulated with Copper Sulfate.

Polyelectrolyte-based ionic-junction fibers newly serve as signal transmission and translation media between electronic devices and biological systems, facilitating ion transport within organic matrices. In this work, we fabricated gel filaments of carboxymethyl cellulose (CMC) chelated with Cu(II) ions through wet-spinning, using a saturated coagulant of CuSO. Interestingly, the as-spun fibers exhibited dramatic 3D porous frameworks that varied with the temperature and precursor concentration.

1β-Hydroxydeoxycholic Acid as an Endogenous Biomarker in Human Plasma for Assessment of CYP3A Clinical Drug-Drug Interaction Potential.

4-Hydroxycholesterol (4-HC) in plasma has been used as a biomarker to assess CYP3A drug-drug interaction (DDI) potential during drug development. However, due to the long half-life and narrow dynamic range of 4-HC, its use has been limited to the identification of CYP3A inducers, but not CYP3A inhibitors. The formation of 1-hydroxydeoxycholic acid (1-OH DCA) from deoxycholic acid (DCA) is mediated by CYP3A, thus 1-OH DCA can potentially serve as an alternative to 4-HC for assessment of CYP3A DDI potential.

3-Dimentional printing of polysaccharides for water-treatment: A review.

Biological polysaccharides such as cellulose, chitin, chitosan, sodium alginate, etc., serve as excellent substrates for 3D printing due to their inherent advantages of biocompatibility, biodegradability, non-toxicity, and absence of secondary pollution. In this review we comprehensively overviewed the principles and processes involved in 3D printing of polysaccharides.

A Pilot Study To Assess the Suitability of Riboflavin As a Surrogate Marker of Breast Cancer Resistance Protein in Healthy Participants.

We recently showed that riboflavin is a selected substrate of breast cancer resistance protein (BCRP) over P-glycoprotein (P-gp) and demonstrated its prediction performance in preclinical drug-drug interaction (DDI) studies. The aim of this study was to investigate the suitability of riboflavin to assess BCRP inhibition in humans. First, we assessed the substrate potential of riboflavin toward other major drug transporters using established transfected cell systems.

Relative bioavailability of fedratinib through various alternative oral administration methods in healthy adults.

Fedratinib is an oral Janus kinase 2-selective inhibitor for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis; however, some patients have difficulty with oral dosing. This randomized, phase 1, open-label, 2-part crossover study evaluated the relative bioavailability, safety, tolerability, taste, and palatability of fedratinib resulting from various alternative oral administration methods in healthy adults. Participants could receive fedratinib 400 mg orally as intact capsules along with a nutritional supplement; as contents of capsules dispersed in a nutritional supplement, delivered via nasogastric tube; or as a divided dose of 200 mg orally twice daily as intact capsules with a nutritional supplement.

2022 White Paper on Recent Issues in Bioanalysis: ICH M10 BMV Guideline & Global Harmonization; Hybrid Assays; Oligonucleotides & ADC; Non-Liquid & Rare Matrices; Regulatory Inputs ( - Recommendations on Mass Spectrometry, Chromatography and Sample Preparation, Novel Technologies, Novel Modalities, and Novel Challenges, ICH M10 BMV Guideline & Global Harmonization - Regulatory Agencies' Inputs on Regulated Bioanalysis/BMV, Biomarkers/CDx/BAV, Immunogenicity, Gene & Cell Therapy and Vaccine).

The 16 Workshop on Recent Issues in Bioanalysis (16 WRIB) took place in Atlanta, GA, USA on September 26-30, 2022. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 16th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccines.

Evaluation of Encequidar as An Intestinal P-gp and BCRP Specific Inhibitor to Assess the Role of Intestinal P-gp and BCRP in Drug-Drug Interactions.

Purpose: The differences between intestinal and systemic (hepatic and renal) P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) roles in drug disposition are difficult to define. Accordingly, we characterized Encequidar (ECD) as an intestinal P-gp and BCRP specific inhibitor to evaluate their role in drug disposition.

Methods: We assessed the in vitro and in vivo inhibition potential of ECD towards human and animal P-gp and BCRP.

White Collar 1 Modulates Oxidative Sensitivity and Virulence by Regulating the HOG1 Pathway in Fusarium asiaticum.

Fusarium asiaticum is an epidemiologically important pathogen of cereal crops in east Asia, accounting for both yield losses and mycotoxin contamination problems in food and feed products. FaWC1, a component of the blue-light receptor White Collar complex (WCC), relies on its transcriptional regulatory zinc finger domain rather than the light-oxygen-voltage domain to regulate pathogenicity of , although the downstream mechanisms remain obscure. In this study, the pathogenicity factors regulated by FaWC1 were analyzed.

Metabolomic Profiling and Drug Interaction Characterization Reveal Riboflavin As a Breast Cancer Resistance Protein-Specific Endogenous Biomarker That Demonstrates Prediction of Transporter Activity In Vivo.

Advancement of endogenous biomarkers for drug transporters as a tool for assessing drug-drug interactions (DDIs) depends on initial identification of biomarker candidates and relies heavily on biomarker validation and its response to reference inhibitors in vivo. To identify endogenous biomarkers of breast cancer resistance protein (BCRP), we applied metabolomic approaches to profile plasma from Bcrp, multidrug resistance protein (Mdr)1a/1b, and Bcrp/Mdr1a/1b mice. Approximately 130 metabolites were significantly altered in Bcrp and P-glycoprotein (P-gp) knockout mice, indicating numerous metabolite-transporter interactions.

A Phase 1, Multicenter, Open-Label Study to Evaluate the Pharmacokinetics of Iberdomide in Subjects with Mild, Moderate, or Severe Hepatic Impairment Compared with Healthy Subjects.

Introduction: Iberdomide, a novel cereblon modulator (CELMoD), is currently under clinical investigation for hematology indications. To evaluate the influence of hepatic impairment on the pharmacokinetics (PK) of iberdomide and its major active metabolite M12, a phase 1, multicenter, open-label study was conducted in healthy subjects and subjects with mild, moderate, and severe hepatic impairment.

Methods: Forty subjects were enrolled in the study and divided into five groups based on hepatic function.

Effects of varying amounts of different biochars on mercury methylation in paddy soils and methylmercury accumulation in rice (Oryza sativa L.).

There is growing evidence for the potential of biochars (BCs) in remediating mercury-contaminated paddy soils, but the high doses commonly used in laboratory studies discourage BC application in practice. To address these difficulties, we compared the effects of varying amounts of BCs from different sources on the formation of methylmercury (MeHg) in soil and its accumulation in rice through microcosm and pot experiments. The addition of a wide range of added doses (0.

Macroscopic Spiral Patterns of Cholesteric Cellulose Nanocrystals Induced by Chiral Doping and Vortex Flowing.

Negatively surface-charged sulfate cellulose nanocrystals (CNCs) are always slowly self-assembled into left-handed cholesteric mesophases. In this work, macroscopic spiral patterns induced by counterclockwise vortex flowing or chiral doping were investigated. Results show that iridescent patterns of the arithmetic spiral, rose spiral, or latitude ripples were generated under the vortex rotation, indicating a severe microphase separation of CNCs.

Propionate poses antivirulence activity against Botrytis cinerea via regulating its metabolism, infection cushion development and overall pathogenic factors.

Botrytis cinerea is a devastating pathogen causing gray mold in fruits and vegetables if not properly managed. Although the mechanisms remain unclear, we previously revealed that the safe food additive calcium propionate (CP) could suppress gray mold development on grapes. The present study reports that sub-lethal dose of CP (0.

Effect of fluconazole on the pharmacokinetics of a single dose of fedratinib in healthy adults.

Purpose: Fedratinib is an orally administered Janus kinase (JAK) 2-selective inhibitor for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis. In vitro, fedratinib is predominantly metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP2C19. Coadministration of fedratinib with CYP3A4 inhibitors is predicted to increase systemic exposure to fedratinib.

Model-based analysis for the population pharmacokinetics of iberdomide and its major active metabolite in healthy subjects and patients with relapsed and refractory multiple myeloma.

Aims: A parent-metabolite population pharmacokinetic (popPK) model of iberdomide and its pharmacologically active metabolite (M12) was developed and the influence of demographic and disease-related covariates on popPK parameters was assessed based on data from 3 clinical studies of iberdomide (dose range, 0.1-6 mg) in healthy subjects (n = 81) and patients with relapsed and refractory multiple myeloma (n 245).

Methods: Nonlinear mixed effects modelling was used to develop the popPK model based on data from 326 subjects across 3 clinical studies.

An Open Label, Phase 1, Randomized, Seven-treatment, Seven-period, Crossover Study to Assess the Relative Bioavailability, pH Effect, Food Effect, and Dose Proportionality of CC-292, a Potent and Orally Available Bruton's Tyrosine Kinase Inhibitor.

Background And Objective: CC-292 is a potent, selective, orally administered small molecule inhibitor of Bruton's tyrosine kinase (BTK). To support the clinical investigation of CC-292, a randomized, seven-treatment, seven-period, crossover study was conducted to assess the relative bioavailability, pH effect, food effect, and dose-proportionality of two formulated tablets of CC-292.

Methods: Healthy subjects (n = 24) were enrolled in the study and randomly assigned into different treatment sequences.