PMID- 38345530 OWN - NLM STAT- MEDLINE DCOM- 20240424 LR - 20240424 IS - 2160-7648 (Electronic) IS - 2160-763X (Linking) VI - 13 IP - 5 DP - 2024 May TI - Safety, Pharmacokinetics, and Pharmacodynamics of Etrasimod: Single and Multiple Ascending Dose Studies in Healthy Adults. PG - 534-548 LID - 10.1002/cpdd.1379 [doi] AB - Etrasimod is an investigational, once-daily, oral, selective sphingosine 1-phosphate receptor 1,4,5 modulator in development for immune-mediated inflammatory diseases (IMIDs). Here, we report the human safety, pharmacokinetics, and pharmacodynamics of etrasimod obtained from both a single ascending dose (SAD; 0.1-5 mg) study and a multiple ascending dose (MAD; 0.35-3 mg once daily) study. Overall, 99 healthy volunteers (SAD n = 40, MAD n = 59) completed the 2 studies. Evaluated single and multiple doses were well tolerated up to 3 mg without severe adverse events (AEs). Gastrointestinal disorders were the most common etrasimod-related AEs. Over the evaluated single- and multiple-dose ranges, dose-proportional and marginally greater-than-dose-proportional etrasimod plasma exposure were observed, respectively. At steady state, etrasimod oral clearance and half-life mean values ranged from 1.0 to 1.2 L/h and 29.7 to 36.4 hours, respectively. Dose-dependent total peripheral lymphocyte reductions occurred following etrasimod single and multiple dosing. Etrasimod multiple dosing resulted in reductions from baseline in total lymphocyte counts ranging from 41.1% to 68.8% after 21 days. Lymphocyte counts returned to normal range within 7 days following treatment discontinuation. Heart rate lowering from pretreatment baseline on etrasimod dosing was typically mild, with mean reductions seen after the first dose of up to 19.5 bpm (5 mg dose). The favorable safety, pharmacokinetic, and pharmacodynamic properties of etrasimod in humans supported its further development and warranted its investigation for treatment of IMIDs. CI - (c) 2024 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology. FAU - Lee, Caroline A AU - Lee CA AD - Arena Pharmaceuticals, A Wholly Owned Subsidiary of Pfizer Inc, San Diego, CA, USA. FAU - Schreiber, Stefan AU - Schreiber S AD - Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany. AD - Excellence Cluster Precision Medicine in Inflammation, Christian-Albrecht University of Kiel, Kiel, Germany. FAU - Bressler, Brian AU - Bressler B AD - Department of Medicine, Division of Gastroenterology, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada. FAU - Adams, John W AU - Adams JW AD - Arena Pharmaceuticals, A Wholly Owned Subsidiary of Pfizer Inc, San Diego, CA, USA. FAU - Oh, Dooman Alexander AU - Oh DA AD - Arena Pharmaceuticals, A Wholly Owned Subsidiary of Pfizer Inc, San Diego, CA, USA. FAU - Tang, Yong Q AU - Tang YQ AD - Arena Pharmaceuticals, A Wholly Owned Subsidiary of Pfizer Inc, San Diego, CA, USA. FAU - Zhang, Jinkun AU - Zhang J AD - Arena Pharmaceuticals, A Wholly Owned Subsidiary of Pfizer Inc, San Diego, CA, USA. FAU - Komori, Heather Kiyomi AU - Komori HK AD - Arena Pharmaceuticals, A Wholly Owned Subsidiary of Pfizer Inc, San Diego, CA, USA. FAU - Grundy, John S AU - Grundy JS AD - Arena Pharmaceuticals, A Wholly Owned Subsidiary of Pfizer Inc, San Diego, CA, USA. LA - eng GR - Arena Pharmaceuticals, San Diego, CA/ PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20240212 PL - United States TA - Clin Pharmacol Drug Dev JT - Clinical pharmacology in drug development JID - 101572899 RN - 0 (Sphingosine 1 Phosphate Receptor Modulators) RN - 0 (Sphingosine-1-Phosphate Receptors) SB - IM MH - Humans MH - Adult MH - Male MH - Female MH - *Healthy Volunteers MH - Young Adult MH - Middle Aged MH - *Dose-Response Relationship, Drug MH - Half-Life MH - Administration, Oral MH - Double-Blind Method MH - Sphingosine 1 Phosphate Receptor Modulators/administration & dosage/pharmacokinetics/adverse effects/pharmacology MH - Drug Administration Schedule MH - Sphingosine-1-Phosphate Receptors MH - Adolescent MH - Area Under Curve OTO - NOTNLM OT - etrasimod OT - inflammatory disease OT - lymphocyte OT - pharmacokinetics OT - sphingosine 1-phosphate receptor EDAT- 2024/02/12 15:44 MHDA- 2024/04/24 14:20 CRDT- 2024/02/12 10:13 PHST- 2023/10/05 00:00 [received] PHST- 2023/12/27 00:00 [accepted] PHST- 2024/04/24 14:20 [medline] PHST- 2024/02/12 15:44 [pubmed] PHST- 2024/02/12 10:13 [entrez] AID - 10.1002/cpdd.1379 [doi] PST - ppublish SO - Clin Pharmacol Drug Dev. 2024 May;13(5):534-548. doi: 10.1002/cpdd.1379. Epub 2024 Feb 12.