Pharmacokinetics, Pharmacodynamics and Antiviral Efficacy of the MEK Inhibitor Zapnometinib in Animal Models and in Humans.

Autor: Koch-Heier J; Department of Immunology, Interfaculty Institute for Cell Biology, Eberhard Karls University Tuebingen, Tuebingen, Germany.; Atriva Therapeutics GmbH, Tuebingen, Germany., Schönsiegel A; Department of Immunology, Interfaculty Institute for Cell Biology, Eberhard Karls University Tuebingen, Tuebingen, Germany.; Atriva Therapeutics GmbH, Tuebingen, Germany., Waidele LM; Department of Immunology, Interfaculty Institute for Cell Biology, Eberhard Karls University Tuebingen, Tuebingen, Germany.; Atriva Therapeutics GmbH, Tuebingen, Germany., Volk J; Department of Immunology, Interfaculty Institute for Cell Biology, Eberhard Karls University Tuebingen, Tuebingen, Germany.; Atriva Therapeutics GmbH, Tuebingen, Germany., Füll Y; Atriva Therapeutics GmbH, Tuebingen, Germany., Wallasch C; Atriva Therapeutics GmbH, Tuebingen, Germany., Canisius S; Atriva Therapeutics GmbH, Tuebingen, Germany., Burnet M; Synovo GmbH, Tuebingen, Germany., Planz O; Department of Immunology, Interfaculty Institute for Cell Biology, Eberhard Karls University Tuebingen, Tuebingen, Germany.; Atriva Therapeutics GmbH, Tuebingen, Germany.
Jazyk: angličtina
Zdroj: Frontiers in pharmacology [Front Pharmacol] 2022 Jun 15; Vol. 13, pp. 893635. Date of Electronic Publication: 2022 Jun 15 (Print Publication: 2022).
DOI: 10.3389/fphar.2022.893635
Abstrakt: The mitogen-activated protein kinase (MEK) inhibitor zapnometinib is in development to treat acute viral infections like COVID-19 and influenza. While the antiviral efficacy of zapnometinib is well documented, further data on target engagement/pharmacodynamics (PD) and pharmacokinetics (PK) are needed. Here, we report zapnometinib PK and PD parameters in mice, hamsters, dogs, and healthy human volunteers. Mice received 25 mg/kg/day zapnometinib (12.5 mg/kg p. o. twice daily, 8 h interval). Syrian hamsters received 30 mg/kg (15 mg/kg twice daily) or 60 mg/kg/day once daily. Beagle dogs were administered 300 mg/kg/day, and healthy human volunteers were administered 100, 300, 600 and 900 mg zapnometinib (once daily p. o.). Regardless of species or formulation, zapnometinib maximum plasma concentration (C max ) was reached between 2-4 h after administration with an elimination half-life of 4-5 h in dogs, 8 h in mice or hamsters and 19 h in human subjects. Doses were sufficient to cause up to 80% MEK inhibition. Across all species approximately 10 μg/ml zapnometinib was appropriate to inhibit 50% of peripheral blood mononuclear cells (PBMC) MEK activity. In mice, a 50%-80% reduction of MEK activity was sufficient to reduce influenza virus titer in the lungs by more than 90%. In general, while >50% MEK inhibition was reached in vivo at most doses, 80% inhibition in PBMCs required significantly higher doses and appeared to be the practical maximal level obtained in vivo . However, the period of reduced phosphorylated extracellular-signal regulated kinase (pERK), a measure of MEK inhibition, was maintained even after elimination of zapnometinib from plasma, suggesting a sustained effect on MEK consistent with regulatory effects or a slow off-rate. These data suggest a target plasma C max of at least 10 μg/ml zapnometinib in further clinical studies.
Competing Interests: OP, CW and SC are shareholder of Atriva Therapeutics GmbH. OP and SC are consultants for Atriva Therapeutics GmbH. CW, JK-H, AS, LW, JV, and YF are employees of Atriva Therapeutics GmbH. MB is managing director of Synovo GmbH.
(Copyright © 2022 Koch-Heier, Schönsiegel, Waidele, Volk, Füll, Wallasch, Canisius, Burnet and Planz.)
Databáze: MEDLINE
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