A Phase 1 First-in-Human Pharmacokinetic and Pharmacodynamic Study of JNJ-64264681, a Covalent Inhibitor of Bruton's Tyrosine Kinase.

Autor: Leu JH; Janssen Research & Development, LLC, Spring House, Pennsylvania, USA., Miao X; Janssen Research & Development, LLC, Spring House, Pennsylvania, USA., Shalayda K; Janssen Research & Development, LLC, Raritan, New Jersey, USA., Coe KJ; Janssen Research & Development, LLC, San Diego, California, USA., Kahnt A; Janssen Research & Development, Beerse, Belgium., Wu B; Janssen Research & Development, LLC, Spring House, Pennsylvania, USA., Schnarr M; Janssen Research & Development, LLC, Spring House, Pennsylvania, USA., Franks C; Janssen Research & Development, LLC, Spring House, Pennsylvania, USA., Devlin J; Janssen Research & Development, LLC, Spring House, Pennsylvania, USA., Yang TY; Janssen Research & Development, LLC, Spring House, Pennsylvania, USA., Palmer JA; Janssen Research & Development, LLC, San Diego, California, USA., Zhang M; Janssen Research & Development, LLC, San Diego, California, USA., Zhou H; Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.; Present affiliation: Kira Pharmaceuticals, Cambridge, Massachusetts, USA., Van Damme W; Clinical Pharmacology Unit, Janssen Research & Development, Merksem, Belgium., Smets S; Clinical Pharmacology Unit, Janssen Research & Development, Merksem, Belgium., Aguilar Z; Janssen Research & Development, LLC, San Diego, California, USA., Chaplan SR; Janssen Research & Development, LLC, San Diego, California, USA.
Jazyk: angličtina
Zdroj: Clinical pharmacology in drug development [Clin Pharmacol Drug Dev] 2023 Jun; Vol. 12 (6), pp. 611-624. Date of Electronic Publication: 2023 May 01.
DOI: 10.1002/cpdd.1253
Abstrakt: JNJ-64264681 is an irreversible covalent inhibitor of Bruton's tyrosine kinase. This phase 1, first-in-human, 2-part (single-ascending dose [SAD]; multiple-ascending dose [MAD]) study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD; Bruton's tyrosine kinase occupancy [BTKO]) of JNJ-64264681 oral solution in healthy participants. For SAD (N = 78), 6 increasing doses of JNJ-64264681 (4-400 mg) or placebo were evaluated in fasted males. The effects of sex, food, and a capsule formulation were evaluated in separate cohorts. For MAD (N = 27), sequential cohorts of male and female participants received 36/100/200 mg JNJ-64264681 once daily for 10 days. JNJ-64264681 exposure (peak concentration; area under the concentration-time curve) was less than dose proportional from 4 mg to 36 mg. Dose-normalized area under the concentration-time curves following the 36 mg and 100 mg doses were generally similar. The mean terminal half-life was 1.6-13.2 hours. With multiple doses, steady state was achieved by day 2. A semimechanistic PK/PD model was developed using the first 5 SAD cohorts' data to predict %BTKO in MAD cohorts. PK/PD model guided dose-escalation, and all participants in the 200/400 mg single-dose cohorts achieved ≥90% BTKO at 4 hours after dosing (peak) with prolonged occupancy. As BTKO data became available from MAD cohorts, it was found that observed BTKO data were consistent with model predictions. JNJ-64264681 showed no safety signals of concern. Overall, safety, tolerability, PK, BTKO, and PK/PD modeling guided the rationale for dose selection for the subsequent first-in-patient lymphoma studies.
(© 2023 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)
Databáze: MEDLINE
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