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.