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

Julia Koch-Heier; Annika Schönsiegel; Lara Maria Waidele; Julian Volk; Yvonne Füll; Christian Wallasch; Sebastian Canisius; Michael Burnet; Oliver Planz

doi:10.3389/fphar.2022.893635

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

Front Pharmacol. 2022 Jun 15:13:893635. doi: 10.3389/fphar.2022.893635. eCollection 2022.

Authors

Julia Koch-Heier^{1

2}, Annika Schönsiegel^{1

2}, Lara Maria Waidele^{1

2}, Julian Volk^{1

2}, Yvonne Füll², Christian Wallasch², Sebastian Canisius², Michael Burnet³, Oliver Planz^{1

2}

Affiliations

¹ Department of Immunology, Interfaculty Institute for Cell Biology, Eberhard Karls University Tuebingen, Tuebingen, Germany.
² Atriva Therapeutics GmbH, Tuebingen, Germany.
³ Synovo GmbH, Tuebingen, Germany.

Abstract

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.

Keywords: MEK inhibitor; WES; antiviral therapy; pharmacodynamic; pharmacokinetic; zapnometinib.