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The metabolic fate of izencitinib, a gut-selective pan-JAK inhibitor, in humans. Identification of unusual fecal metabolites and implications for MIST evaluation

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Abstract

Izencitinib is a novel, orally administered pan-JAK inhibitor designed as a gut-selective therapy that was under development for the treatment of inflammatory bowel disease. The objectives of this study were to define the mass balance, routes and rates of excretion, and metabolic fate of izencitinib after oral administration of [14C]-izencitinib in humans. Six healthy adult male subjects were administered a single 100 mg (~300 μCi) oral dose of [14C]-izencitinib. Fecal excretion was the dominant route of elimination with >90% of the administered dose recovered in the feces. As expected by design, plasma concentrations of total radioactivity and izencitinib were low with the mean terminal half-life of total radioactivity (138 h) exceeding that of izencitinib (32.4 h). Izencitinib represented approximately 17% of the total circulating radioactivity, suggesting the presence of multiple circulating plasma metabolites. However, no individual metabolite exceeded 10% of total drug-related material in plasma. The major metabolites in feces, M18 and M9, were found to have unusual structures that reflected the presence of a nucleophilic carbon center in the naphthyridine ring of izencitinib. Proposed mechanisms for the formation of these metabolites involved oxidation and rearrangement (M18) and a one-carbon addition, potentially occurring through reaction with endogenous formaldehyde. Given the gut-selective properties of izencitinib, it is proposed that these novel fecal metabolites are the most relevant for evaluating the impact of metabolism on the pharmacological and toxicological properties of izencitinib, and that the circulating plasma metabolite profile is of little consequence in the assessment of the safety characteristics of izencitinib metabolites.

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Abbreviations

ADME:

absorption, distribution, metabolism, and excretion

AMS:

accelerator mass spectrometry

AUC:

area under the curve

AUC0-96h :

area under the curve from time zero to 96 hours

AUC0-t :

area under the curve from time zero to the last measured concentration

CID:

collision induced dissociation

Cmax :

maximum concentration

CD:

Crohn’s disease

FTIH:

first-time-in human

GFP-STAT1:

green fluorescent protein-signal transducer and activator of transcription

GI:

gastrointestinal

h:

hour or hours

HLM:

human liver microsomes

HPLC:

high-performance liquid chromatography

HPLC-UV/MS:

HPLC coupled with mass spectrometry and ultraviolet detection

HRMS:

high resolution mass spectra

IBD:

inflammatory bowel disease

IC50 :

half maximal inhibitory concentration

JAK:

Janus kinase

Ki:

dissociation constant

LC-MS/MS:

HPLC with tandem mass spectrometry LC-UV/AMS

MHRA:

Medicines and Healthcare products Regulatory Agency

MIST:

metabolites in safety testing

MS3 :

third generation product ions mass spectrometry

ND:

not detected

1H NMR:

nuclear magnetic resonance

PDA:

photodiode array

pIC50 :

negative log of IC50

pKi:

negative log of Ki

PK:

pharmacokinetics

RP:

reverse phase

t1/2 :

half life

Tmax :

time of maximum concentration

S.D.:

standard deviation

SEM:

standard error of the mean

UC:

ulcerative colitis

UV:

ultraviolet

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Acknowledgements

The authors and Theravance Biopharma thank the subjects for their participation in the clinical trial, and the principal investigator and clinical site staff at Celerion, Inc. in Lincoln, Nebraska. The study was funded by Theravance Biopharma Ireland Limited.

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Author notes

  1. Suresh Yeola

    Present address: Theravance Biopharma US, Inc., South San Francisco, CA, USA

  2. These authors contributed equally: Suresh Yeola, Ilaria Badagnani

Authors and Affiliations

  1. Theravance Biopharma US, Inc., South San Francisco, CA, USA

    Ilaria Badagnani, Xiaojun Huang, Nathanial L. Segraves, Miroslav Rapta, Marie T. Borin, Glenmar P. Obedencio & David L. Bourdet

  2. Division of Gastroenterology and Hepatology, Stanford School of Medicine, Stanford, CA, USA

    William L. Fitch

  3. Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA, 98195, USA

    Thomas A. Baillie

  4. Biotransformase, Drug Metabolism Consulting LLC, Roswell, GA, USA

    Suresh Yeola

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Contributions

IB, GPO, MR, and DLB are employees of Theravance Biopharma US, Inc., and shareholders in Theravance Biopharma, Inc. MTB, WLF, TAB are paid consultants for Theravance Biopharma US, Inc. SY, NLS, and XH are former employees of Theravance Biopharma US, Inc., and may hold shares in Theravance Biopharma, Inc.

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Correspondence to David L. Bourdet.

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Yeola, S., Badagnani, I., Huang, X. et al. The metabolic fate of izencitinib, a gut-selective pan-JAK inhibitor, in humans. Identification of unusual fecal metabolites and implications for MIST evaluation. Med Chem Res 32, 2071–2088 (2023). https://doi.org/10.1007/s00044-023-03143-6

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