RESUMO
Janus kinase (JAK) signaling has been implicated in human inflammatory diseases, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. Lorpucitinib (JNJ-64251330) is an oral, small molecule, pan-JAK inhibitor. Unlike systemic JAK antagonists, lorpucitinib was found to have enteric (gut)-selective properties, providing possible applications in diseases of the human gastrointestinal tract. Here, lorpucitinib was evaluated in a phase I, two-part, dosing study (NCT04552197) to assess pharmacokinetics, pharmacodynamic biomarkers, and safety in healthy participants. In part 1, 24 participants were randomized to 1 of 4 treatment arms receiving either lorpucitinib (30 mg daily, 30 mg every 12 hours (q12h), or 75 mg q12h) or tofacitinib (5 mg q12h) for 5 days. Part 2 was a food-effect study in which 12 participants received a single 75-mg dose of lorpucitinib under either fasting or fed conditions. In part 1, plasma and gut tissue concentrations of lorpucitinib showed approximately dose-proportional increases. At all doses, lorpucitinib concentrations were significantly higher (392- to 1928-fold) in the gut mucosal biopsies vs. the corresponding plasma samples, demonstrating high enteric selectivity and significantly exceeding both the tissue concentrations (> 200-fold) and tissue/plasma ratios observed with tofacitinib. JAK inhibition in biopsies was confirmed via reduction in pSTAT-3 levels. In part 2, lorpucitinib plasma concentrations were detectable but at low levels, with no statistical differences in PK parameters between the fed and fasted groups. Lorpucitinib was safe and well-tolerated, and the data may be useful in designing studies to evaluate lorpucitinib in patients with JAK/STAT-driven gastrointestinal diseases.
