Impact of the Mucin Barrier on the In Vitro Membrane Permeability of Cyclic Peptides.

This study investigated the role of the mucin layer in cyclic peptide permeability using an in vitro assay system. We evaluated the membrane permeability of 18 cyclic peptides and reference compounds using biosimilar mucin and Caco2/HT29 cells. The permeability of paracellular markers (FD4 and LY) and digoxin (a low molecular weight compound) remained unaffected by mucin presence when using biosimilar mucin.

Development and validation of highly sensitive ligand binding assay to measure soluble DLL3 concentration in human serum.

Background: Delta-like protein 3 (DLL3) is considered to inhibit the Notch pathway in the tumorigenesis of small cell lung cancer (SCLC) and other neuroendocrine carcinomas, making it a potential therapeutic target in the treatment of cancer. Since the soluble form (sDLL3) is expected to be useful for predicting the status of DLL3 expression on tumors, analytical methods to measure sDLL3 are required.

Research Design And Methods: Assay methods using ELISA and the SMCxPRO platform were developed to analyze sDLL3 concentration in human serum.

Robust and reproducible human intestinal organoid-derived monolayer model for analyzing drug absorption.

Predicting the absorption of orally administered drugs is crucial to drug development. Current in vitro models lack physiological relevance, robustness, and reproducibility, thus hindering reliable predictions. In this study, we developed a reproducible and robust culture method to generate a human intestinal organoid-derived monolayer model that can be applied to study drug absorption through a step-by-step approach.

Quantitative prediction of drug disposition for uridine diphosphate-glucuronosyltransferase substrates using humanized mice.

Drug clearance and drug-drug interactions are essential for pharmacokinetic assessment. However, current in vitro systems and animal scale-up approaches often fail to accurately predict drug disposition mediated by metabolizing enzymes, especially uridine diphosphate-glucuronosyltransferase (UGT). This study demonstrates how UGT-mediated drug disposition in humans can be predicted using hu-PXB mice (cDNA-uPA/severe combined immunodeficiency (SCID) mice transplanted with human-derived hepatocytes).

Quantitative prediction of CYP3A-mediated drug-drug interactions by correctly estimating fraction metabolized using human liver chimeric mice.

Background And Purpose: Fraction metabolized (f ) and fraction transported (f ) are important for understanding drug-drug interactions (DDIs) in drug discovery and development. However, current in vitro systems cannot accurately estimate in vivo f due to inability to reflect the f by efflux transporters (f ). This study demonstrates how CYP3A-mediated DDI for CYP3A/P-gp substrates can be predicted using Hu-PXB mice as human liver chimeric mice.

Fibroblast inhibition by tocilizumab enabled gemcitabine/nab-paclitaxel rechallenge for pancreatic cancer.

Interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway inhibition may overcome chemoresistance of metastatic pancreatic cancer (MPC). We sought to determine the safety and recommended dose of tocilizumab (TCZ), an IL-6 receptor monoclonal antibody, and biological correlates of tumor shrinkage in patients with gemcitabine (GEM)/nanoparticle albumin-bound paclitaxel (nab-PTX)-refractory MPC. This phase 1 study enrolled 10 patients with MPC who had progressed after GEM/nab-PTX.

Development of rat duodenal monolayer model with effective barrier function from rat organoids for ADME assay.

The in-depth analysis of the ADME profiles of drug candidates using in vitro models is essential for drug development since a drug's exposure in humans depends on its ADME properties. In contrast to efforts in developing human in vitro absorption models, only a limited number of studies have explored models using rats, the most frequently used species in in vivo DMPK studies. In this study, we developed a monolayer model with an effective barrier function for ADME assays using rat duodenal organoids as a cell source.

Maxacalcitol Pharmacokinetic-Pharmacodynamic Modeling and Simulation for Secondary Hyperparathyroidism in Patients Receiving Maintenance Hemodialysis.

Background: Maxacalcitol was approved in Taiwan in 2018 as the first active vitamin D3 injection for secondary hyperparathyroidism (SHPT) in patients on maintenance hemodialysis. However, no data from any clinical study with maxacalcitol in Taiwanese patients is available.

Objectives: This analysis aimed to evaluate the profiles of parathyroid hormone (PTH) and calcium (Ca) concentrations in Taiwanese SHPT patients on hemodialysis and maxacalcitol.

Effects of Child-Pugh B Cirrhosis on Pharmacokinetics of Tofogliflozin, a New Sodium-Glucose Co-Transporter (SGLT2) Inhibitor.

Background: Tofogliflozin is a highly selective sodium-glucose co-transporter 2 (SGLT2) inhibitor. A mass balance study with combinations of microdoses revealed that tofogliflozin has high oral bioavailability (97.5%) and that tofogliflozin in circulation is eliminated primarily by metabolic pathways, with the liver playing a prominent role in elimination.

Simulating the Impact of Elevated Levels of Interleukin-6 on the Pharmacokinetics of Various CYP450 Substrates in Patients with Neuromyelitis Optica or Neuromyelitis Optica Spectrum Disorders in Different Ethnic Populations.

A physiologically based pharmacokinetic (PBPK) model was used to simulate the impact of elevated levels of interleukin (IL)-6 on the exposure of several orally administered cytochrome P450 (CYP) probe substrates (caffeine, S-warfarin, omeprazole, dextromethorphan, midazolam, and simvastatin). The changes in exposure of these substrates in subjects with rheumatoid arthritis (and hence elevated IL-6 levels) compared with healthy subjects were predicted with a reasonable degree of accuracy. The PBPK model was then used to simulate the change in oral exposure of the probe substrates in North European Caucasian, Chinese, and Japanese population of patients with neuromyelitis optica (NMO) or NMO spectrum disorder with elevated plasma IL-6 levels (up to 100 pg/mL).

Pharmacokinetics and Pharmacodynamics of Tofogliflozin (a Selective SGLT2 Inhibitor) in Healthy Male Subjects.

Tofogliflozin is a selective oral inhibitor of sodium-glucose co-transporter 2 for treatment of type 2 diabetes mellitus. The pharmacokinetics, pharmacodynamics, and safety of tofogliflozin were investigated in healthy male subjects. Three studies were conducted: single-ascending dose study (10-640 mg) in 56 Japanese and 24 Caucasian subjects; multiple-ascending dose study (2.

Clinical pharmacology of tocilizumab for the treatment of polyarticular-course juvenile idiopathic arthritis.

The efficacy and safety of tocilizumab (TCZ), a humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibody, in patients with polyarticular-course juvenile idiopathic arthritis (pJIA) were demonstrated in clinical trials. Area covered: A literature search was undertaken in the public domain from 1995 to 2016. Data included in the regulatory submission leading to approval of TCZ for the treatment of pJIA in the European Union, United States, and Japan were also presented.

Characterization of patients with advanced pancreatic cancer and high serum interleukin-6 levels.

Objectives: High serum level of interleukin 6 (IL-6) is associated with high degree of tumor progression and systemic weakness. Anti-IL-6 therapy possibly improves the deterioration of clinical characteristics in patients with high IL-6 level. However, IL-6-related factors in patients with treatment-naive advanced pancreatic cancer (PC) have not been established.

Immune response to influenza vaccine and pneumococcal polysaccharide vaccine under IL-6 signal inhibition therapy with tocilizumab.

Objectives: To evaluate humoral immune response to influenza vaccine and polysaccharide pneumococcal vaccine in patients with rheumatoid arthritis (RA) or Castleman's disease (CD) during tocilizumab therapy.

Methods: Thirty-eight patients (28 RA and 10 CD) receiving tocilizumab and 39 RA patients receiving TNF inhibitors and/or synthetic DMARDs subcutaneously received a single dose of a split-virion inactivated influenza vaccine containing A(New Caledonia (NC):H1N1), A(Hiroshima (HIR):H3N2) and B(Malaysia (MAL)) strains. Twenty-one RA patients using tocilizumab also received 23-valent polysaccharide pneumococcal vaccine.

Mechanism-based approach using a biomarker response to evaluate tocilizumab subcutaneous injection in patients with rheumatoid arthritis with an inadequate response to synthetic DMARDs (MATSURI study).

A multicenter, open-label, dose-escalation phase 1/2 study was undertaken to evaluate the optimal subcutaneous tocilizumab dose that would result in exposure comparable to the intravenous tocilizumab 8-mg/kg approved dose in patients with rheumatoid arthritis. A pharmacokinetic and biomarker approach was used to estimate the clinical optimal dose regimen of subcutaneous tocilizumab. Safety and efficacy of subcutaneous tocilizumab were assessed as secondary end points.

Clinical pharmacology of tocilizumab for the treatment of systemic juvenile idiopathic arthritis.

Tocilizumab is a humanized anti-IL-6 receptor monoclonal antibody approved for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis. Biweekly doses of 8 mg/kg for patients who weigh ≥ 30 kg and 12 mg/kg for patients who weigh <30 kg produce adequate blockade of IL-6 receptors and normalization of C-reactive protein levels. The mean area under the curve during a 2-week dosing interval, maximum and minimum serum concentrations for both doses were 1341 ± 415 µg·day/ml, 245 ± 57.

Associations of interleukin-6 with vegetative but not affective depressive symptoms in terminally ill cancer patients.

Purpose: Previous studies have reported associations of depressive symptoms with pro-inflammatory cytokines, especially with interleukin-6 (IL-6) in noncancer subjects and cancer patients. Meanwhile, symptoms such as tiredness and appetite loss may be vegetative symptoms of depression when associated with other diagnostic criteria of depression. Such vegetative-type symptoms worsen during the last 6 months of life in cancer patients and may not be associated with affective depressive symptoms such as sadness and nervousness.

Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease.

Interleukin-6 (IL-6) plays pathologic roles in immune-inflammatory diseases such as rheumatoid arthritis (RA) and Castleman disease. By inhibiting IL-6 receptors (IL-6Rs), tocilizumab (a humanized anti-IL-6R antibody) ameliorates the symptoms of these diseases and normalizes acute-phase proteins, including C-reactive protein (CRP). We found that tocilizumab treatment increased serum levels of IL-6 and soluble IL-6R (sIL-6R).