Pharmacokinetics, Safety, and Tolerability of GS‐1427, an Oral Prodrug of a Potent and Selective α4β7 Integrin Inhibitor, in Healthy Participants

GS‐1427 is the oral prodrug of GS‐1069518, an inhibitor of the α4β7 integrin, and is currently in development for the treatment of ulcerative colitis (UC). This first‐in‐human, phase 1, placebo‐controlled study evaluated the pharmacokinetics, safety, and tolerability of GS‐1427 and GS‐1069518 after single oral doses (20‐1000 mg) or multiple once‐daily doses (20‐500 mg) of GS‐1427 for 14 days. The bioavailability of tablet versus capsule formulations and the effect of food and an acid‐reducing agent (omeprazole) on exposure were also assessed. Overall, 148 healthy participants were enrolled, and 143 completed the study. GS‐1427 was quickly converted to GS‐1069518 during absorption. Upon repeated once‐daily dosing of GS‐1427 under nonfasting conditions, steady‐state exposure to GS‐1069518 was reached by day 5 with limited accumulation observed. At steady state, the median time to maximum concentration for GS‐1069518 was 1‐3 h and the mean terminal half‐life was 6.7‐28.3 h. Bioavailability was lower in the tablet than in capsule formulation. Food intake and omeprazole coadministration reduced the exposure to GS‐1069518 by approximately 20%‐40%. Overall, 26/122 participants (21.3%) who received GS‐1427 and 8/26 participants (30.1%) who received placebo experienced at least one treatment‐emergent adverse event (AE). Of the 148 participants, 10 (6.8%) experienced a treatment‐related AE, the most common being nausea (5/148, 3.4%) and diarrhea (3/148, 2.0%). All AEs were grade 1 in severity and no serious AEs or deaths were reported. The pharmacokinetics, safety, and tolerability results from this study support further evaluation of GS‐1427 in a phase 2 trial in patients with UC.