Single‑Dose Pharmacokinetics and Safety of the Oral Galectin‑3 Inhibitor, Selvigaltin (GB1211), in Participants with Hepatic Impairment.

Background And Objectives: Selvigaltin (GB1211), an orally available small molecule galectin-3 inhibitor developed as a treatment for liver fibrosis and cirrhosis, was evaluated to assess the effect of hepatic impairment on its pharmacokinetics and safety to address regulatory requirements.

Methods: GULLIVER-2 was a Phase Ib/IIa three-part study. Parts 1 and 3 had single-dose, open-label designs assessing pharmacokinetics (plasma [total and unbound] and urine), safety, and tolerability of 100 mg oral selvigaltin in participants with moderate (Child-Pugh B, Part 1) or severe (Child-Pugh C, Part 3) hepatic impairment, compared with healthy-matched participants (n = 6 each).

A proof of concept using the Ussing chamber methodology to study pediatric intestinal drug transport and age-dependent differences in absorption.

Little is known about the impact of age on the processes governing human intestinal drug absorption. The Ussing chamber is a system to study drug transport across tissue barriers, but it has not been used to study drug absorption processes in children. This study aimed to explore the feasibility of the Ussing chamber methodology to assess pediatric intestinal drug absorption.

Review of paediatric gastrointestinal physiology relevant to the absorption of orally administered medicines.

Despite much progress in regulations to improve paediatric drug development, there remains a significant need to develop better medications for children. For the design of oral dosage forms, a detailed understanding of the specific gastrointestinal (GI) conditions in children of different age categories and how they differ from GI conditions in adults is essential. Several review articles have been published addressing the ontogeny of GI characteristics, including luminal conditions in the GI tract of children.

Ontogeny of Small Intestinal Drug Transporters and Metabolizing Enzymes Based on Targeted Quantitative Proteomics.

Most drugs are administered to children orally. An information gap remains on the protein abundance of small intestinal drug-metabolizing enzymes (DMEs) and drug transporters (DTs) across the pediatric age range, which hinders precision dosing in children. To explore age-related differences in DMEs and DTs, surgical leftover intestinal tissues from pediatric and adult jejunum and ileum were collected and analyzed by targeted quantitative proteomics for apical sodium-bile acid transporter, breast cancer resistance protein (BCRP), monocarboxylate transporter 1 (MCT1), multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein (MRP) 2, MRP3, organic anion-transporting polypeptide 2B1, organic cation transporter 1, peptide transporter 1 (PEPT1), CYP2C19, CYP3A4, CYP3A5, UDP glucuronosyltransferase (UGT) 1A1, UGT1A10, and UGT2B7.

Impact of In Vitro Passive Permeability in a P-gp-transfected LLC-PK1 Model on the Prediction of the Rat and Human Unbound Brain-to-Plasma Concentration Ratio.

Purpose: More accurate prediction of the extent of drug brain exposure in early drug discovery and understanding potential species differences could help to guide medicinal chemistry and avoid unnecessary animal studies. Hence, the aim of the current study was to validate the use of a P-gp transfected LLC-PK1 model to predict the unbound brain-to-plasma concentration ratio (Kp) in rats and humans.

Methods: MOCK-, Mdr1a- and MDR1-transfected LLC-PK1 monolayers were applied in a transwell setup to quantify the bidirectional transport for 12 specific P-gp substrates, 48 UCB drug discovery compounds, 11 compounds with reported rat in situ brain perfusion data and 6 compounds with reported human Kp values.