Abstract
Purpose
Pemigatinib (INCB054828), a potent and selective oral fibroblast growth factor receptor 1–3 inhibitor, is a Biopharmaceutical Classification System class II compound with good permeability and pH-dependent solubility that is predominantly metabolized by cytochrome P450 (CYP) 3A. Two drug-drug interaction studies, one with acid-reducing agents, esomeprazole (proton pump inhibitor [PPI]) and ranitidine (histamine-2 [H2] antagonist), and the other with potent CYP3A-modulating agents, itraconazole (CYP3A inhibitor) and rifampin (CYP3A inducer), were performed.
Methods
Both were open-label, fixed-sequence studies conducted in up to 36 healthy participants each, enrolled into two cohorts (n = 18 each). Pemigatinib plasma concentration was measured, and pharmacokinetic parameters were derived by non-compartmental analysis.
Results
There was an 88% and 17% increase in pemigatinib area under the plasma drug concentration–time curve (AUC) and maximum plasma drug concentration (Cmax), respectively, with itraconazole, and an 85% and 62% decrease in pemigatinib AUC and Cmax with rifampin coadministration. There was a 35% and 8% decrease in pemigatinib AUC and Cmax, respectively, with esomeprazole, and a 2% decrease in Cmax and 3% increase in AUC with ranitidine coadministration. In both studies, all adverse events reported were grade ≤ 2.
Conclusion
Coadministration with itraconazole or rifampin resulted in a clinically significant change in pemigatinib exposure. Therefore, coadministration of strong CYP3A inducers with pemigatinib should be avoided, and the dose of pemigatinib should be reduced if coadministration with strong CYP3A inhibitors cannot be avoided. The effect of PPIs/H2 antagonists on pemigatinib exposure was modest, and pemigatinib can be administered without regard to coadministration of PPIs/H2 antagonists.
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Availability of data and material
The datasets generated during and/or analyzed during the current study are available from the corresponding author (email: tji@incyte.com) on reasonable request.
Change history
26 August 2021
A Correction to this paper has been published: https://doi.org/10.1007/s00228-021-03198-7
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Acknowledgements
The authors thank the participants, investigators, and site personnel who participated in these studies. Editorial assistance was provided by Envision Pharma Group, Inc. (Philadelphia, PA, USA).
Funding
The study was funded by Incyte Corporation, Wilmington, DE, USA.
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Tao Ji, Naresh Punwani, Xuejun Chen, and Swamy Yeleswaram were involved in the conception/design of the work. Kevin Rockich, Noam Epstein, Heather Overholt, and Phillip Wang acquired the data. Tao Ji analyzed the data. All the authors drafted the manuscript or revised it critically for important intellectual content, and approved the manuscript.
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Both studies were performed in accordance with the International Council for Harmonization guideline for Good Clinical Practice, including the Declaration of Helsinki and local ethical and legal requirements.
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All participants provided written informed consent before initiating treatment.
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Tao Ji, Kevin Rockich, Heather Overholt, Phillip Wang, Xuejun Chen, Naresh Punwani, and Swamy Yeleswaram are employees/stockholders of Incyte Corporation. Noam Epstein is an employee/stockholder of GlaxoSmithKline.
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Ji, T., Rockich, K., Epstein, N. et al. Evaluation of drug-drug interactions of pemigatinib in healthy participants. Eur J Clin Pharmacol 77, 1887–1897 (2021). https://doi.org/10.1007/s00228-021-03184-z
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DOI: https://doi.org/10.1007/s00228-021-03184-z