Safety and pharmacokinetics of GB1211, an oral galectin-3 inhibitor: a single- and multiple-dose first-in-human study in healthy participants.

PURPOSE: Galectin-3, a ß-galactoside-binding lectin, plays a key role in several cellular pathways involved in chronic inflammation, heart disease and cancer. GB1211 is an orally bioavailable galectin-3 inhibitor, developed to be systemically active. We report safety and pharmacokinetics (PK) of GB1211 in healthy participants. METHODS: This phase 1, double-blind, placebo-controlled, first-in-human study (NCT03809052) included a single ascending-dose phase (with a food-effect cohort) where participants across seven sequential cohorts were randomized 3:1 to receive oral GB1211 (5, 20, 50, 100, 200 or 400 mg) or placebo. In the multiple ascending-dose phase, participants received 50 or 100 mg GB1211 or placebo twice daily for 10 days. All doses were administered in the fasted state except in the food-effect cohort where doses were given 30 min after a high-fat meal. RESULTS: All 78 participants received at least one GB1211 dose (n = 58) or placebo (n = 20) and completed the study. No safety concerns were identified. Following single and multiple oral doses under fasted conditions, maximum GB1211 plasma concentrations were reached at 1.75-4 h (median) post-dose; mean half-life was 11-16 h. There was a ~ twofold GB1211 accumulation in plasma with multiple dosing, with steady-state reached within 3 days; 30% of the administered dose was excreted in urine as unchanged drug. Absorption in the fed state was delayed by 2 h but systemic exposure was unaffected. CONCLUSION: GB1211 was well tolerated, rapidly absorbed, and displayed favorable PK, indicating a potential to treat multiple disease types. These findings support further clinical development of GB1211. CLINICAL TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov (identifier: NCT03809052).

In Vitro-In Vivo Correlations Observed With Indacaterol-Based Formulations Delivered with the Breezhaler®.

BACKGROUND: Establishing robust in vitro-in vivo correlations (IVIVC) between aerosol performance, pharmacokinetics, and clinical efficacy is critical in developing bioequivalent drug-device combination products. Recent studies have demonstrated that realistic throat models tested under realistic test conditions may provide good IVIVC with respect to total lung deposition. METHODS: The Alberta idealized throat (AIT) model was utilized with mean peak inspiratory flow rates determined from patient breathing studies. Various formulations of indacaterol (e.g., lactose blends, fixed dose combinations, engineered PulmoSphere™ particles) were tested in the AIT model and in clinical pharmacokinetic studies. RESULTS: Good IVIVC were observed with respect to total lung deposition, systemic delivery, and the contribution of oral absorption to systemic delivery, with percentage differences from the mean in vivo measurements <15%, with most comparisons <5%. CONCLUSIONS: Anatomical throat models represent an exciting tool to aid in formulation development of pharmaceutical aerosols.