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

• Published in: Clinical drug investigation 2024-10, Vol.44 (10), p.773-787
• Main Authors: Aslanis, Vassilios, Gray, Michael, Slack, Robert J., Zetterberg, Fredrik R., Tonev, Dimitar, Phung, De, Smith, Becky, Jacoby, Brian, Schambye, Hans, Krastev, Zahari, Ungell, Anna-Lena, Lindmark, Bertil
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Aged; Blood Proteins - metabolism; Drug dosages; Female; Galectin 3 - antagonists & inhibitors; Galectin 3 - blood; Galectins - antagonists & inhibitors; Humans; Internal Medicine; Liver cirrhosis; Liver diseases; Liver Diseases - metabolism; Male; Medicine; Medicine & Public Health; Metabolism; Metabolites; Middle Aged; NCT; NCT05009680; Original Research Article; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Plasma
• ISSN: 1173-2563; 1179-1918; 1179-1918
• DOI: 10.1007/s40261-024-01395-7

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). Results All participants received selvigaltin and completed the study. No adverse events were reported. The median time to reach maximum total plasma concentration following drug administration was of 3.49 and 4.00 h post-dose for Child-Pugh B and C participants, respectively; comparable with controls. Total plasma exposure was higher for participants with hepatic impairment compared with controls. Whilst maximum plasma concentration ( C max ) was unaffected in Child-Pugh B participants, area under the plasma concentration-time curve from time zero to infinity (AUC ∞ ) increased by ~ 1.7-fold compared with controls, and half-life was prolonged (geometric mean 28.15 vs 16.38 h). In Child-Pugh C participants, C max increased by ~ 1.3-fold, AUC ∞ increased by ~ 1.5-fold, and half-life was prolonged (21.05 vs 16.14 h). No trend was observed in plasma unbound fractions or urinary excretion of unchanged selvigaltin in either group. Conclusion Hepatic impairment increased selvigaltin exposure without safety concerns. These data can inform dose recommendations for future clinical programmes. Trial Registration Clinicaltrials.gov NCT05009680.