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

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 (Cmax) 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 Cmax of at least 10 μg/ml zapnometinib in further clinical studies.

Pharmacokinetics, absorption, distribution, metabolism and excretion of the MEK inhibitor zapnometinib in rats

“…Many of the hydroxylated metabolites were subsequently glucuronidated leading to a fast excretion in the feces (Wabnitz et al, 2004). Since glucuronidation was not observed to such an extend with zapnometinib in rats, this could be a reason for a prolonged presence of zapnometinib in animals and humans compared to CI-1040 (Lorusso et al, 2005;Koch-Heier et al, 2022). In summary, the metabolic profile confirms the good stability and bioavailability with normal metabolization of the compound for elimination of the drug from the body, demonstrating an important role for metabolizing enzymes for the ADME profile of zapnometinib, Determined by oxidation and liquid scintillation analysis (LLOQ = 0.011-0.031 µg equiv zapnometinib/g).…”

“…Zapnometinib is an orally available MEK-inhibitor with a dual therapeutic effect that is currently under development for the treatment of severe viral diseases like COVID-19 and influenza. Preclinical in vitro and in vivo studies demonstrated efficacy and safety of the drug ( Laure et al, 2020 ; Schreiber et al, 2022 ; Koch-Heier et al, 2022 ), which allowed further investigations in Phase 1 (NCT04385420) and Phase 2 (NCT04776044) clinical trials in humans. Zapnometinib is the active metabolite of CI-1040, a drug that was developed to treat cancer ( LoRusso et al, 2005 , Rinehart et al, 2004 ; Barrett et al, 2008 ; Seibold-Leopold et al 1999).…”

“…In a plasma protein binding assay in human, dog and rat plasma, zapnometinib showed high protein binding, and a very low unbound fraction (data not shown). Nevertheless, the compound shows good efficacy when PK and PD were correlated ( Koch-Heier et al, 2022 ). A possible interaction with albumin, serving as a drug-carrier and reservoir for the molecule, is further investigated.…”

“…Pharmacokinetics and pharmacodynamics of zapnometinib were already investigated in animal models and in humans. Here, it could be shown that MEK inhibition was maintained even after elimination of zapnometinib from plasma ( Koch-Heier et al, 2022 ). Zapnometinib was already studied in a phase 1 clinical trial (NCT04385420) demonstrating a favorable pharmacokinetic, safety and toxicology profile.…”

Establishment of a novel method to assess MEK1/2 inhibition in PBMCs for clinical drug development

“…Ras activates Raf, which then phosphorylates MEK1 and MEK2. Activated MEK1/2 subsequently activates ERK1 and ERK2 through phosphorylation ( Sebolt-Leopold et al, 1999 ; Planz, 2013 ; Koch-Heier et al, 2022 ). ERK1/2 constitutes the only known substrate of MEK1/2 ( Lorusso et al, 2005 ; Yoon and Seger, 2006 ; Koch-Heier et al, 2022 ) and eventually influences proliferation, differentiation, apoptosis and survival ( Sebolt-Leopold, 2004 ; Lorusso et al, 2005 ; Meier et al, 2005 ; Yoon & Seger, 2006 ), but also cytokine production and cellular immune responses ( Ludwig et al, 2003 ; Planz, 2013 ; Koch-Heier et al, 2022 ).…”