Evaluation of the Effect of Food on the Pharmacokinetics of SHR6390, An Oral CDK4/6 Inhibitor, in Healthy Volunteers
Yan-Ping Liu, Ming-Hui Hu, Ping-Ping Lin, Ting Li, Shu-Qin Liu, Yu-Ya Wang, Shao-Rong Li, Xiang-Kun Li, Chen-Jing Wang, Yu Cao, Yan-Ping Liu, Ming-Hui Hu, Ping-Ping Lin, Ting Li, Shu-Qin Liu, Yu-Ya Wang, Shao-Rong Li, Xiang-Kun Li, Chen-Jing Wang, Yu Cao
Abstract
Background and introduction: SHR6390 is a new developed highly effective and selective small-molecule oral CDK4/6 inhibitor. We aimed to evaluate the effect of food on the pharmacokinetics of SHR6390 tablets.
Methods: In an open-label two-way crossover study, 24 healthy Chinese volunteers were randomly divided into Group A and Group B, and 12 volunteers in each group received a single oral dose of a SHR6390 150-mg tablet under fasting and high-fat conditions. Blood samples were collected and determined for pharmacokinetic analyses. A liquid chromatography-tandem mass spectrometry method was developed and validated for determining the SHR6390 concentration.
Results: The time to maximum plasma concentration was not significantly affected by a high-fat diet. Compared with the fasting group, maximum plasma concentration, i.e., the area under the concentration-time curve (AUC0-t and AUC0-∞) was altered significantly, as evidenced by an increase of 56.9%, 38.6%, and 37.5% respectively. We identified seven metabolites of SHR6390 from the plasma samples, and we found no sex differences in metabolic pathways. All treatment-emergent adverse events were Grade 1 or 2.
Conclusions: Food intake increased the maximum plasma concentration, AUC0-t, and AUC0-∞ significantly compared with the fasting condition. Meanwhile, single-dose SHR6390 for two treatment cycles is safe. SHR6390 was administered in a fasting status in the pivotal phase III study (NCT03927456) and chosen for the final drug label.
Conflict of interest statement
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in, or financial conflict with, the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
© 2022. The Author(s).
Figures
References
- Lange CA, Yee D. Killing the second messenger: targeting loss of cell cycle control in endocrine-resistant breast cancer. Endocr Relat Cancer. 2011;18:C19–24. doi: 10.1530/ERC-11-0112.
- Friend SH, Bernards R, Rogelj S, et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986;323:643–646. doi: 10.1038/323643a0.
- Harbour JW, Lai SL, Whang-Peng J, et al. Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science. 1988;241:353–357. doi: 10.1126/science.2838909.
- Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol. 2006;24:1770–1783. doi: 10.1200/JCO.2005.03.7689.
- Burdette-Radoux S, Tozer RG, Lohmann RC, et al. Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma. Invest New Drugs. 2004;22(3):315–322. doi: 10.1023/B:DRUG.0000026258.02846.1c.
- Arnold A, Papanikolaou A. Cyclin D1 in breast cancer pathogenesis. J Clin Oncol. 2005;23(18):4215–4224. doi: 10.1200/JCO.2005.05.064.
- Santarius T, Shipley J, Brewer D, et al. A census of amplified and overexpressed human cancer genes. Nat Rev Cancer. 2010;10(1):59–64. doi: 10.1038/nrc2771.
- Liggett WH, Jr, Sidransky D. Role of the p16 tumor suppressor gene in cancer. J Clin Oncol. 1998;16(3):1197–1206. doi: 10.1200/JCO.1998.16.3.1197.
- US Food and Drug Administration. Guidance for industry: food-effect bioavailability and fed bioequivalence studies (last updated: December 2002). . Accessed 27 Aug 2018.
- US Food and Drug Administration. Guidance for industry: assessing the effects of food on drugs in INDs and NDAs: clinical pharmacology considerations. . Accessed 28 Apr 2022.
- Ruiz-Garcia A, Plotka A, O’Gorman M, et al. Effect of food on the bioavailability of palbociclib. Cancer Chemother Pharmacol. 2017;79(3):527–533. doi: 10.1007/s00280-017-3246-4.
Source: PubMed