Target Occupancy and Functional Inhibition of JAK3 and TEC Family Kinases by Ritlecitinib in Healthy Adults: An Open-Label, Phase 1 Study.

Autor: Martin DA; Pfizer Inc., Cambridge, MA, USA., Telliez JB; Pfizer Inc., Cambridge, MA, USA., Pleasic-Williams S; Pfizer Inc., Groton, CT, USA., Zhang Y; Pfizer Inc., Groton, CT, USA., Tierney B; Pfizer Inc., Groton, CT, USA., Blatnik M; Pfizer Inc., Groton, CT, USA., Gale JD; Pfizer Inc., Cambridge, MA, USA., Banfield C; Pfizer Inc., Cambridge, MA, USA., Zhou Y; Pfizer Inc., Collegeville, PA, USA., Lejeune A; Pfizer Inc., Paris, France., Zwillich SH; Pfizer Inc., Groton, CT, USA., Stevens E; Pfizer Inc., Groton, CT, USA., Tiwari N; Pfizer Inc., New Haven, CT, USA., Kieras E; Pfizer Inc., Cambridge, MA, USA., Karanam A; Pfizer Inc., Cambridge, MA, USA.
Jazyk: angličtina
Zdroj: Journal of clinical pharmacology [J Clin Pharmacol] 2024 Jan; Vol. 64 (1), pp. 67-79. Date of Electronic Publication: 2023 Sep 29.
DOI: 10.1002/jcph.2347
Abstrakt: Ritlecitinib is a small molecule in clinical development that covalently and irreversibly inhibits Janus kinase 3 (JAK3) and the TEC family of kinases (BTK, BMX, ITK, TXK, and TEC). This phase 1, open-label, parallel-group study assessed target occupancy and functional effects of ritlecitinib on JAK3 and TEC family kinases in healthy participants aged 18-60 years who received 50 or 200 mg single doses of ritlecitinib on day 1. Blood samples to assess ritlecitinib pharmacokinetics, target occupancy, and pharmacodynamics were collected over 48 hours. Target occupancy was assessed using mass spectroscopy. Functional inhibition of JAK3-dependent signaling was measured by the inhibition of the phosphorylation of its downstream target signal transducer and activator of transcription 5 (pSTAT5), following activation by interleukin 15 (IL-15). The functional inhibition of Bruton's tyrosine kinase (BTK)-dependent signaling was measured by the reduction in the upregulation of cluster of differentiation 69 (CD69), an early marker of B-cell activation, following treatment with anti-immunoglobulin D. Eight participants received one 50 mg ritlecitinib dose and 8 participants received one 200 mg dose. Ritlecitinib plasma exposure increased in an approximately dose-proportional manner from 50 to 200 mg. The maximal median JAK3 target occupancy was 72% for 50 mg and 64% for 200 mg. Ritlecitinib 50 mg had >94% maximal target occupancy of all TEC kinases, except BMX (87%), and 200 mg had >97% for all TEC kinases. For BTK and TEC, ritlecitinib maintained high target occupancy throughout a period of 48 hours. Ritlecitinib reduced pSTAT5 levels following IL-15- and BTK-dependent signaling in a dose-dependent manner. These target occupancy and functional assays demonstrate the dual inhibition of the JAK3- and BTK-dependent pathways by ritlecitinib. Further studies are needed to understand the contribution to clinical effects of inhibiting these pathways.
(© 2023 Pfizer Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)
Databáze: MEDLINE
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