Abstract
Introduction
FCN-159 is a novel, oral, potent, selective MEK1/2 inhibitor in clinical development for the treatment of NRAS-mutant advanced melanoma and neurofibromatosis type 1. We investigated the effect of food on the pharmacokinetics (PK), safety, and tolerability of FCN-159.
Methods
In this single-center, open-label, phase 1 study with a three-period, three-sequence, crossover design, healthy Chinese male subjects (n = 24) were randomized (1:1:1) to receive a single, oral 8 mg dose of FCN-159 in the fasted state (overnight, > 10 h), and with a low-fat and a high-fat meal, separated by a 10-day washout. PK parameters including time to maximum plasma concentration (Cmax) and area under the concentration–time curve (AUC) were compared using geometric least-squares mean ratios (GLSMR), with the fasted state as the reference. A 90% CI for the GLSMR within 80–125% indicated no significant food effect.
Results
A low-fat meal (n = 23) did not affect the PK profile of FCN-159: G LSMR for AUC from time 0 to t (AUC0–t), 106.9% (90% CI 99.9–114.4%); AUC from time 0 to infinity (AUC0–∞), 106.8% (90% CI 100.0–114.0%); Cmax, 96.4% (90% CI 83.9–110.8%). A high-fat meal (n = 24) did not affect exposure to FCN-159 (GLSMR for AUC0–t, 99.4%; 90% CI 99.0–106.3%; AUC0–∞, 99.5 5%; 90% CI 93.2–106.1%), but modestly reduced Cmax by 15% (GLSMR 84.9%; 90% CI 74.0–97.3%). Both the low-fat and high-fat meals slightly prolonged the median time to Cmax by 0.5 h (90% CI 0.5–1.0 h). FCN-159 was generally well tolerated, with a lower incidence of treatment-emergent adverse events following administration in the fasted state than with a low-fat or high-fat meal (20.8%, 39.1%, and 37.5%, respectively).
Conclusion
Food did not affect the PK profile of FCN-159 to a clinically meaningful extent compared with administration in the fasted state.
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Acknowledgements
Funding
This study was funded by Shanghai Fosun Pharmaceutical Development Co., Ltd. The study sponsor also funded the journal’s Rapid Service fees.
Medical Writing, Editorial, and Other Assistance
Editorial support for this manuscript was provided by Jake Burrell PhD (Rude Health Consulting Ltd.) and paid for by Fosun Pharma.
Author Contributions
Xuhong Wang, Lei Diao, Jiangfan Li, Yan Tan, Kexin Li, Yan Tan, Ai-Min Hui, Zhuli Wu, and Pu Han contributed to the study design, study conduct, and the critical review of the intellectual content of the article, and approved the final version for publication. Zheng Wei and Jingjun Qiu contributed to the analysis and interpretation of data, the critical review of the intellectual content of the article, and approved the final version for publication.
Disclosures
Yan Tan, Zhuli Wu, Pu Han, Zhen Wei, Jingjun Qiu, and Lei Diao are employees of Beijing Fosun Pharmaceutical Research and Development Co., Ltd. Ai-Min Hui is an employee of Fosun Pharma USA Inc. The other authors declare that they have no conflicts of interest.
Compliance with Ethics Guidelines
The study protocol was approved by the Ethics Review Board at Beijing Luhe Hospital, Capital Medical University, Beijing, China (approval number: 2021-LHYW-062-01). The study was conducted in compliance with applicable laws in China, and in accordance with the Chinese Guidelines for Good Clinical Practice and the principles outlined in the Declaration of Helsinki of 1964 and subsequent revisions. All subjects provided written, informed consent prior to participation. This paper was written following the ClinPK guidelines.
Data Availability
The datasets generated during the current study are available from the corresponding author on reasonable request.
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Li, J., Tan, Y., Li, K. et al. Effect of Food (Low and High Fat) on Pharmacokinetics of FCN-159, a Selective MEK Inhibitor, in Healthy Chinese Males. Adv Ther 40, 1074–1086 (2023). https://doi.org/10.1007/s12325-022-02375-z
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DOI: https://doi.org/10.1007/s12325-022-02375-z