Metabolism, excretion, and pharmacokinetics of [14C]INCB018424, a selective Janus tyrosine kinase 1/2 inhibitor, in humans
Abstract
The metabolism, excretion, and pharmacokinetics of 3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile (INCB018424), a potent, selective inhibitor of Janus tyrosine kinase1/2 and the first investigational drug of its class in phase III studies for the treatment of myelofibrosis, were investigated in healthy human subjects given a single oral 25-mg dose of [(14)C]INCB018424 as an oral solution. INCB018424 and total radioactivity were absorbed rapidly (mean time to reach the maximal drug concentration 70% within 24 h postdose) with 74 and 22% recovered in urine and feces, respectively. Parent compound was the predominant entity in the circulation, representing 58 to 74% of the total radioactivity up to 6 h postdose, indicating that the overall circulating metabolite burden was low ( 95% absorbed. In healthy subjects administered daily oral doses of unlabeled INCB018424, there were minimal differences in parent and metabolite concentrations between day 1 and day 10, indicating a lack of accumulation of parent or metabolites between single and multiple dosing.
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Ruxolitinib has rapid metabolism and a short half-life.
“thus counteracting its rapid metabolism (Shilling et al., 2010) resulting in its short half-life (Shi et al., 2011).”
From Model Based Targeting of IL-6-Induced Inflammatory Responses in Cultured Primary Hepatocytes to Improve Application of the JAK Inhibitor Ruxolitinib (2017) · cites this paper as Shilling et al., 2010
Cites
Lin, Q., Meloni, D., Pan, Y., Xia, M., Rodgers, J., Shepard, S., Li, M., Galya, L., Metcalf, B., Yue, T.-Y., et al. (2009) · Organic Letters · doi:10.1021/ol900350k · Cited by 171 · see citing works
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Sobotta, S., Raue, A., Huang, X., Vanlier, J., Jünger, A., Bohl, S., Albrecht, U., Hahnel, M. J., Wolf, S., Mueller, N. S., et al. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00775 · Cited by 28 · see citing works
“Specifically, a model-predicted treatment with a high initial bolus and two following lower doses is necessary for a longterm effect of the clinically applied inhibitor Ruxolitinib, thus counteracting its rapidmetabolism (Shilling et al., 2010) resulting in its short half-life (Shi et al., 2011).”
BackgroundAssessment of Skin Toxicity in an in Vitro Reconstituted Human Epidermis Model Using Deep Learning
Hu, F., Santagostino, S. F., Danilenko, D. M., Tseng, M., Brumm, J., Zehnder, P., & Wu, K. C. (2022) · The American Journal of Pathology · doi:10.1016/j.ajpath.2021.12.007 · Cited by 13 · see citing works
- Authors
- Shilling, A. D., Nedza, F. M., Emm, T., Diamond, S., McKeever, E., Punwani, N., Williams, W., Arvanitis, A., Galya, L. G., Li, M., Shepard, S., Rodgers, J., Yue, T.-Y., & Yeleswaram, S.
- Affiliations
- Incyte (United States) (US)
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2010-11
- Volume
- 38
- Issue
- 11
- Pages
- 2023-2031
- ISSN
- 0090-9556 (ISSN-L)
- OpenAlex
- W2059200513
- Cited by
- 111
- References
- 1
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 2 · 2023: 6 · 2022: 10 · 2021: 8 · 2020: 4 · 2019: 4 · 2018: 4 · 2017: 6 · 2016: 12 · 2015: 8 · 2014: 9 · 2013: 14 · 2012: 10
- FWCI
- 10.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Keywords
- JAK1/2 inhibitor, myelofibrosis, pharmacokinetics, drug metabolism, metabolite identification, glucuronide conjugates, oral bioavailability, drug accumulation, healthy volunteers, radiolabeled drug, drug efficacy, oral solution, adverse events, tolerability
- MeSH terms
- Chromatography, High Pressure Liquid, Dose-Response Relationship, Drug, Double-Blind Method, Enzyme Inhibitors, Feces, Female, Humans, Male, Metabolic Clearance Rate, Nitriles, Pyrazoles, Pyrimidines, Molecular Structure, Janus Kinase 1, Janus Kinase 2, Tandem Mass Spectrometry
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