Serum Bile Acid Elevation is an Independently Associated With Pruritus in Patients With At-risk Metabolic Dysfunction-associated Steatotic Liver Disease.

Background And Aims: Elevated serum bile acids are associated with pruritus in cholestatic liver diseases. We assessed the association of serum bile acids and other putative biomarkers of cholestatic pruritus (autotaxin and interleukin-31 (IL-31) with pruritus in patients with metabolic dysfunction-associated steatotic liver disease (MASLD).

Methods: We used serum from patients with MASLD and metabolic dysfunction-associated steatohepatitis (MASH), viral hepatitis B, viral hepatitis C, and healthy blood donors to measure the levels of bile acids, autotaxin, and IL-31.

Analysis of C4 Concentrations to Predict Impact of Patient-Reported Diarrhea Associated With the Ileal Bile Acid Transporter Inhibitor Linerixibat.

Linerixibat, an ileal bile acid transporter (IBAT) inhibitor, is being evaluated for the treatment of pruritus in primary biliary cholangitis (PBC). Diarrhea is commonly reported with this drug class as IBAT inhibition redirects bile acids (BA) to the colon. Serum 7-alpha-hydroxy-4-cholesten-3-one (C4) measurement is a validated method to identify BA diarrhea.

Serum bile acid change correlates with improvement in pruritus in patients with primary biliary cholangitis receiving linerixibat.

Background & Aims: Total serum bile acid (TSBA) levels are elevated in patients with primary biliary cholangitis (PBC) and may mediate cholestatic pruritus. Linerixibat, an ileal bile acid transporter inhibitor, improved pruritus in patients with PBC. We explored the relationship between linerixibat dose, TSBA concentration, and pruritus.

Physiologically Based Biopharmaceutics Model (PBBM) of Minimally Absorbed Locally Acting Drugs in the Gastrointestinal Tract-Case Study: Tenapanor.

A physiologically based biopharmaceutics model (PBBM) was developed to predict stool and urine sodium content in response to tenapanor administration in healthy subjects. Tenapanor is a minimally absorbed small molecule that inhibits the sodium/hydrogen isoform 3 exchanger (NHE3). It is used to treat irritable bowel syndrome with constipation (IBS-C).

Population Dose-Response-Time Analysis of Itch Reduction and Patient-Reported Tolerability Supports Phase III Dose Selection for Linerixibat.

Increase in serum bile acids (BAs) in patients with primary biliary cholangitis (PBC) may play a causal role in cholestatic pruritus (itch). Linerixibat is a selective small molecule inhibitor of the ileal bile acid transporter, which blocks re-absorption of BAs in the gastrointestinal tract thereby lowering BAs in the systemic circulation and reducing itch. One consequence is excess BAs in the colon, leading to diarrhea and abdominal pain.

Clinical assessment of gepotidacin (GSK2140944) as a victim and perpetrator of drug-drug interactions via CYP3A metabolism and transporters.

Gepotidacin is a novel triazaacenaphthylene antibiotic in phase III development. Based on nonclinical in vitro characterization of gepotidacin metabolism, two phase I studies were conducted in healthy participants to investigate clinical drug-drug interactions (DDIs). We assessed gepotidacin as a DDI victim with a potent cytochrome P450 (CYP) 3A4/P-glycoprotein (P-gp) inhibitor (itraconazole), potent CYP3A4 inducer (rifampicin), and nonspecific organic cation transporter (OCT)/multidrug and toxic extrusion transporter (MATE) renal transport inhibitor (cimetidine) via single doses of gepotidacin before and after co-administration with multiple doses of the modulator drugs.

Dose selection for a phase III study evaluating gepotidacin (GSK2140944) in the treatment of uncomplicated urogenital gonorrhoea.

Background: Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and is active against most strains of (). Phase II data suggested higher exposures were needed for efficacy and to suppress resistance development. A translational approach using in vitro pharmacokinetic/pharmacodynamic (PK/PD) and clinical data was used to select a gepotidacin dose for a phase III study.

GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus.

Background & Aims: GLIMMER assessed dose-response, efficacy, and safety of linerixibat, an ileal bile acid transporter inhibitor in development for cholestatic pruritus associated with primary biliary cholangitis (PBC).

Methods: GLIMMER was a Phase 2b, multicenter, randomized, parallel-group study in adults with PBC and moderate-to-severe pruritus (≥4 on 0-10 numerical rating scale [NRS]). After 4 weeks of single-blind placebo, patients with NRS ≥3 were randomized (3:1) to double-blind linerixibat/placebo for 12 weeks (to week 16), followed by single-blind placebo (to week 20).

Pharmacokinetics, safety, and tolerability of gepotidacin administered as single or repeat ascending doses, in healthy adults and elderly subjects.

Gepotidacin, a novel, first-in-class triazaacenaphthylene antibiotic, inhibits bacterial DNA replication by a distinct mechanism of action. We report the pharmacokinetics (PKs), safety, and tolerability of gepotidacin following single or multiple ascending doses. Studies 1 and 2 were randomized, single-blind, placebo-controlled trials in healthy adults aged 18-60 years, who received single (study 1 [NCT02202187]; 100-3000 mg) or repeat (study 2 [NCT01706315]; 400 mg twice daily to 2000 mg thrice daily) ascending doses of gepotidacin.

Pharmacokinetics and ADME Characterization of Intravenous and Oral [C]-Linerixibat in Healthy Male Volunteers.

Linerixibat, an oral small-molecule ileal bile acid transporter inhibitor under development for cholestatic pruritus in primary biliary cholangitis, was designed for minimal absorption from the intestine (site of pharmacological action). This study characterized the pharmacokinetics, absorption, metabolism, and excretion of [C]-linerixibat in humans after an intravenous microtracer concomitant with unlabeled oral tablets and [C]-linerixibat oral solution. Linerixibat exhibited absorption-limited flip-flop kinetics: longer oral versus intravenous half-life (6-7 hours vs.

Design and Conduct Considerations for First-in-Human Trials.

A milestone step in translational science to transform basic scientific discoveries into therapeutic applications is the advancement of a drug candidate from preclinical studies to initial human testing. First-in-human (FIH) trials serve as the link to advance new promising drug candidates and are conducted primarily to determine the safe dose range for further clinical development. Cross-functional collaboration is essential to ensure efficient and successful FIH trials.

Innovation at the Intersection of Clinical Trials and Real-World Data Science to Advance Patient Care.

While efficacy and safety data collected from randomized clinical trials are the evidentiary standard for determining market authorization, this alone may no longer be sufficient to address the needs of key stakeholders (regulators, providers, and payers) and guarantee long-term success of pharmaceutical products. There is a heightened interest from stakeholders on understanding the use of real-world evidence (RWE) to substantiate benefit-risk assessment and support the value of a new drug. This review provides an overview of real-world data (RWD) and related advances in the regulatory framework, and discusses their impact on clinical research and development.

Sorafenib hepatobiliary disposition: mechanisms of hepatic uptake and disposition of generated metabolites.

Sorafenib is an orally active tyrosine kinase inhibitor used in the treatment of renal and hepatocellular carcinoma. This study was designed to establish whether transport proteins are involved in the hepatic uptake of sorafenib and to determine the extent of biliary excretion of sorafenib and its metabolites in human hepatocytes. Initial uptake was assessed in freshly isolated, suspended human hepatocytes in the presence of inhibitors and modulators.

Evaluation of (99m)technetium-mebrofenin and (99m)technetium-sestamibi as specific probes for hepatic transport protein function in rat and human hepatocytes.

Purpose: This study characterized 99mTc-Mebrofenin (MEB) and 99mTc-Sestamibi (MIBI) hepatic transport and preferential efflux routes (canalicular vs. basolateral) in rat and human sandwich-cultured hepatocytes (SCH).

Methods: 99mTc-MEB and 99mTc-MIBI disposition was determined in suspended hepatocytes and in SCH in the presence and absence of inhibitors and genetic knockdown of breast cancer resistance protein (Bcrp).

Sandwich-cultured hepatocytes: an in vitro model to evaluate hepatobiliary transporter-based drug interactions and hepatotoxicity.

Sandwich-cultured hepatocytes (SCH) are a powerful in vitro tool that can be utilized to study hepatobiliary drug transport, species differences in drug transport, transport protein regulation, drug-drug interactions, and hepatotoxicity. This review provides an up-to-date summary of the SCH model, including a brief history of, and introduction to, the use of SCH, as well as methodology to evaluate hepatobiliary drug disposition. A summary of the literature that has utilized this model to examine the interplay between drug-metabolizing enzymes and transport proteins, drug-drug interactions at the transport level, and hepatotoxicity as a result of altered hepatic transport also is provided.

Influence of seeding density and extracellular matrix on bile Acid transport and mrp4 expression in sandwich-cultured mouse hepatocytes.

This study was undertaken to examine the influence of seeding density, extracellular matrix and days in culture on bile acid transport proteins and hepatobiliary disposition of the model bile acid taurocholate. Mouse hepatocytes were cultured in a sandwich configuration on six-well Biocoat plates with an overlay of Matrigel (BC/MG) or gelled-collagen (BC/GC) for 3 or 4 days at seeding densities of 1.0, 1.

Integration of preclinical and clinical data with pharmacokinetic modeling and simulation to evaluate fexofenadine as a probe for hepatobiliary transport function.

Purpose: The suitability of fexofenadine as a probe substrate to assess hepatobiliary transport function in humans was evaluated by pharmacokinetic modeling/simulation and in vitro/in situ studies using chemical modulators.

Methods: Simulations based on a pharmacokinetic model developed to describe fexofenadine disposition in humans were conducted to examine the impact of altered hepatobiliary transport on fexofenadine disposition. The effect of GF120918 on fexofenadine disposition was evaluated in human sandwich-cultured hepatocytes (SCH).

Impact of basolateral multidrug resistance-associated protein (Mrp) 3 and Mrp4 on the hepatobiliary disposition of fexofenadine in perfused mouse livers.

The disposition of fexofenadine, a commonly used antihistamine drug, is governed primarily by active transport. Biliary excretion of the parent compound is the major route of systemic clearance. Previous studies demonstrated that fexofenadine hepatic uptake is mediated by organic anion transporting polypeptides.

A non-spherical core in the explosion of supernova SN 2004dj.

An important and perhaps critical clue to the mechanism driving the explosion of massive stars as supernovae is provided by the accumulating evidence for asymmetry in the explosion. Indirect evidence comes from high pulsar velocities, associations of supernovae with long-soft gamma-ray bursts, and asymmetries in late-time emission-line profiles. Spectropolarimetry provides a direct probe of young supernova geometry, with higher polarization generally indicating a greater departure from spherical symmetry.