The pharmacokinetics, pharmacodynamics, and safety of orally dosed INCB018424 phosphate in healthy volunteers
Abstract
INCB018424 phosphate, a potent inhibitor of JAK enzymes with selectivity for JAK1&2, is in development for the treatment of myelofibrosis (MF). The oral dose pharmacokinetics, pharmacodynamics, safety, and tolerability of INCB018424 were evaluated in healthy volunteers in 2 double-blind, randomized, and placebo-controlled studies. The first study evaluated single ascending doses of 5 to 200 mg INCB018424 and the effect of food, whereas the second study evaluated multiple ascending doses, including both once- and twice-daily dosing for 10 days. As a Biopharma-ceutical Classification System class I drug, INCB018424 exhibited good oral bioavailability and dose-proportional systemic exposures. INCB018424 showed low oral dose clearance and a small volume of distribution, with an approximate 3-hour plasma half-life and insignificant accumulation following repeat dosing. A high-fat meal reduced INCB018424 C(max) by 24% but had little effect on INCB018424 AUC. INCB018424 was cleared primarily by metabolism with negligible renal excretion. The pharmacodynamics of INCB018424, evaluated by the inhibition of phosphorylated STAT3 following cytokine stimulation in whole blood, showed good correlation with INCB018424 plasma concentrations. INCB018424 was generally safe and well tolerated, with 25 mg bid and 100 mg qd established as the maximum tolerated doses in healthy volunteers.
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Low neutrophil counts have been observed in 66% of healthy volunteers treated with 100 mg Ruxolitinib daily.
“Since low neutrophil counts have been observed in 66% of healthy volunteers treated with 100 mg Ruxolitinib daily (q24h; Shi et al., 2011), it is of great importance not to exceed the recommended daily doses.”
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 Shi et al., 2011
The efficacy of Ruxolitinib decreased with increasing incubation time.
“In line with the previous observation in a clinical trial (Shi et al., 2011), the efficacy of Ruxolitinib decreased with increasing incubation time.”
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 Shi et al., 2011
Ruxolitinib has a plasma half-life of ~3 h in humans.
“Because Ruxolitinib was reported to have a plasma half-life of ~3 h in humans (Shi et al., 2011), Ruxolitinib degradation was included in the model.”
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 Shi et al., 2011
The maximal tolerable dose of Ruxolitinib in healthy volunteers is 100 mg once daily, already inducing severe side effects such as neutropenia.
“The maximal tolerable dose of Ruxolitinib in healthy volunteers was described to be 100 mg once daily, already inducing severe side effects as neutropenia (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 Shi et al., 2011
Negligible accumulation of Ruxolitinib occurs after multiple doses, minimizing risk of potential side effects.
“Shi et al. found negligible accumulation of Ruxolitinib after multiple doses, thus minimizing the risk of potential side effects.”
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 Shi et al., 2011
Previous treatment planning was based on preclinical data and empirical results from clinical trials.
“Notably, previous treatment planning was based on preclinical data and empirical results from clinical trials (Quintas-Cardama et al., 2010; 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 Shi et al., 2011
Multiple-dose Ruxolitinib treatment with equal doses has a more sustained effect on STAT3 signaling compared with single treatment.
“Multiple-dose Ruxolitinib treatment with equal doses was shown earlier to have a more sustained effect on STAT3 signaling, compared with single treatment (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 Shi et al., 2011
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 Shi et al., 2011
An increase in Ruxolitinib dose is not desirable due to harmful side-effects such as neutropenia.
“an increase in dose is not desirable due to harmful side-effects such as neutropenia (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 Shi et al., 2011
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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
“In line with the previous observation in a clinical trial (Shi et al., 2011), the efficacy of Ruxolitinib decreased with increasing incubation time.”
BackgroundMethodResultInfluential
- Authors
- Shi, J. G., Chen, X., McGee, R. F., Landman, R. R., Emm, T., Lo, Y., Scherle, P. A., Punwani, N. G., Williams, W. V., & Yeleswaram, S.
- Affiliations
- Incyte (United States) (US)
- Corresponding author
- Shi, Jack G.
- Venue
- The Journal of Clinical Pharmacology
- Publisher
- Wiley
- Published
- 2011-12
- Volume
- 51
- Issue
- 12
- Pages
- 1644-1654
- ISSN
- 0021-9754 (ISSN-L)
- 0091-2700
- OpenAlex
- W2142501647
- Cited by
- 168
- References
- 0
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 8 · 2023: 11 · 2022: 25 · 2021: 19 · 2020: 8 · 2019: 9 · 2018: 11 · 2017: 5 · 2016: 7 · 2015: 10 · 2014: 13 · 2013: 14 · 2012: 12
- FWCI
- 7.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Keywords
- JAK1/2 inhibitor, myelofibrosis, oral pharmacokinetics, oral bioavailability, food effect, STAT3 phosphorylation, pharmacodynamics, dose proportionality, maximum tolerated dose, drug safety and tolerability, healthy volunteers
- MeSH terms
- Adolescent, Adult, Biological Availability, Double-Blind Method, Female, Humans, Male, Middle Aged, Neutropenia, Nitriles, Pyrazoles, Pyrimidines, Food-Drug Interactions, Area Under Curve, STAT3 Transcription Factor, Janus Kinases, Young Adult
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