Skip to main content
Springer Nature Link
Log in

Food Effect on the Pharmacokinetics of VC004, a Tropomyosin Receptor Kinase Inhibitor: A Randomized Crossover Trial in Healthy Chinese Subjects

  • Original Research Article
  • Published:
Save article
View saved research
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

Background and Objective

VC004 is a novel next-generation tropomyosin receptor kinase (TRK) inhibitor that is approved for the treatment of advanced or metastatic NTRK fusion-positive solid tumors and abrogated the drug resistance of the first-generation TRK inhibitors. The objective of the present study was to evaluate the effect of food on the pharmacokinetics and safety of VC004.

Methods

The study was a randomized, open-label, two-period crossover, single-dose, phase I clinical trial. A total of 16 healthy subjects participated the trial. Subjects fasted for 10 h before drug administration in both fasting and fed states. Subjects received VC004 50 mg orally in the fasting state and after a high caloric food in the fed state. Blood samples at the designated time points were collected to determine the plasma concentration of VC004. Safety evaluation in both the fasted and fed periods were assessed via vital sign monitoring and clinical laboratory tests.

Results

The maximum plasma concentration (Cmax) of VC004 in fed group decreased by 32.8%, corresponding with the slower absorption rate (time to Cmax (Tmax) delayed by almost 3 h) compared with the fasting group. Ratios of geometric means (GMRs) and 90% confidence intervals (90% CIs) of Cmax, the area under the curve of plasma concentration-time from zero to the last measurable concentration (AUC0–t), and AUC from zero to infinity (AUC0–∞) for VC004 between the two states were 67.18 (58.16–77.60), 103.59 (95.04–112.92) and 103.55 (95.63–112.11), respectively. No serious adverse events (AEs) occurred; only three grade 1 or grade 2 adverse events occurred in the fasted group, who recovered by the end of the study.

Conclusions

The intake of high calorie food decreased the absorption rate and increased the Tmax of VC004, while the AUC values were similar in both groups. No serious adverse event was reported. In conclusion, food does not alter the pharmacokinetics and safety profile of VC004 in a clinically meaningful manner.

Trial Registration

ClinicalTrials.gov ID: NCT055528120.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+
from $39.99 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

References

  1. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15(12):731–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kiss E, Papai Z. Novel targeted therapeutic option in oncology: tropomyosin receptor tyrosine kinase inhibitors. Orv Hetil. 2021;162(34):1362–9.

    Article  PubMed  Google Scholar 

  3. Ahsman MJ, Hanekamp M, Wildschut ED, Tibboel D, Mathot RA. Population pharmacokinetics of midazolam and its metabolites during venoarterial extracorporeal membrane oxygenation in neonates. Clin Pharmacokinet. 2010;49(6):407–19.

    Article  CAS  PubMed  Google Scholar 

  4. Zhuo LS, Wang MS, Wu FX, Xu HC, Gong Y, Yu ZC, Tian YG, Pang C, Hao GF, Huang W, et al. Discovery of next-generation tropomyosin receptor kinase inhibitors for combating multiple resistance associated with protein mutation. J Med Chem. 2021;64(20):15503–14.

    Article  CAS  PubMed  Google Scholar 

  5. Kojadinovic A, Laderian B, Mundi PS. Targeting TRK: A fast-tracked application of precision oncology and future directions. Crit Rev Oncol Hematol. 2021;165: 103451.

    Article  PubMed  Google Scholar 

  6. Harada G, Drilon A. TRK inhibitor activity and resistance in TRK fusion-positive cancers in adults. Cancer Genet. 2022;264–265:33–9.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Scott LJ. Larotrectinib: first global approval. Drugs. 2019;79(2):201–6.

    Article  CAS  PubMed  Google Scholar 

  8. Drilon A, Nagasubramanian R, Blake JF, Ku N, Tuch BB, Ebata K, Smith S, Lauriault V, Kolakowski GR, Brandhuber BJ, et al. A Next-Generation TRK kinase inhibitor overcomes acquired resistance to prior TRK kinase inhibition in patients with TRK Fusion-Positive Solid Tumors. Cancer Discov. 2017;7(9):963–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Veerman GDM, Hussaarts K, Jansman FGA, Koolen SWL, van Leeuwen RWF, Mathijssen RHJ. Clinical implications of food-drug interactions with small-molecule kinase inhibitors. Lancet Oncol. 2020;21(5):e265–79.

    Article  CAS  PubMed  Google Scholar 

  10. Fan Y, Zhang Y, Liu Y, Jiang H, Zhou Y, Tang C, Fan W. Pyrizolo[1,5-a]pyrimidine derivatives of the second-generation TRK inhibitor: design, synthesis and biological evaluation. Bioorg Med Chem Lett. 2022;63: 128646.

    Article  CAS  PubMed  Google Scholar 

  11. Meneses-Lorente G, Bentley D, Guerini E, Kowalski K, Chow-Maneval E, Yu L, Brink A, Djebli N, Mercier F, Buchheit V, et al. Characterization of the pharmacokinetics of entrectinib and its active M5 metabolite in healthy volunteers and patients with solid tumors. Invest New Drugs. 2021;39(3):803–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Aepala MR, Peiris MN, Jiang Z, Yang W, Meyer AN, Donoghue DJ. Nefarious NTRK oncogenic fusions in pediatric sarcomas: Too many to Trk. Cytokine Growth Factor Rev. 2022;68:93–106.

    Article  CAS  PubMed  Google Scholar 

  13. Singh BN, Malhotra BK. Effects of food on the clinical pharmacokinetics of anticancer agents: underlying mechanisms and implications for oral chemotherapy. Clin Pharmacokinet. 2004;43(15):1127–56.

    Article  CAS  PubMed  Google Scholar 

  14. Ratain MJ. Importance of food effects for oral oncology drugs. Clin Adv Hematol Oncol. 2012;10(6):397–8.

    PubMed  Google Scholar 

  15. Tistaert C, Heimbach T, Xia B, Parrott N, Samant TS, Kesisoglou F. Food Effect Projections via Physiologically Based Pharmacokinetic Modeling: Predictive Case Studies. J Pharm Sci. 2019;108(1):592–602.

    Article  CAS  PubMed  Google Scholar 

  16. Parrott N, Stillhart C, Lindenberg M, Wagner B, Kowalski K, Guerini E, Djebli N, Meneses-Lorente G. Physiologically Based Absorption Modelling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Entrectinib. AAPS J. 2020;22(4):78.

    Article  CAS  PubMed  Google Scholar 

  17. Jiang Q, Li M, Li H, Chen L. Entrectinib, a new multi-target inhibitor for cancer therapy. Biomed Pharmacother. 2022;150: 112974.

    Article  CAS  PubMed  Google Scholar 

  18. Hong DS, DuBois SG, Kummar S, Farago AF, Albert CM, Rohrberg KS, van Tilburg CM, Nagasubramanian R, Berlin JD, Federman N, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020;21(4):531–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank Jiangsu Vcare PharmaTech-Co., Ltd, especially Xiaojuan Lai and Yanchun Gong who reviewed the English grammar. The authors also thank the participating volunteers and investigators who contributed to this work.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Nanjing Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China

    Linlin Hu

  2. Department of Phase I Clinical Trial Unit, Nanjing Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China

    Linlin Hu, Qiuyue Sun, Lu Tang, Mingmin Cai, Wei Qian, Ting Dou & Huiping Wang

  3. Jiangsu Vcare PharmaTech Co., Ltd., Nanjing, China

    Yong Wu & Yongqiang Liu

Authors
  1. Linlin Hu
    View author publications

    Search author on:PubMed Google Scholar

  2. Qiuyue Sun
    View author publications

    Search author on:PubMed Google Scholar

  3. Lu Tang
    View author publications

    Search author on:PubMed Google Scholar

  4. Mingmin Cai
    View author publications

    Search author on:PubMed Google Scholar

  5. Wei Qian
    View author publications

    Search author on:PubMed Google Scholar

  6. Ting Dou
    View author publications

    Search author on:PubMed Google Scholar

  7. Huiping Wang
    View author publications

    Search author on:PubMed Google Scholar

  8. Yong Wu
    View author publications

    Search author on:PubMed Google Scholar

  9. Yongqiang Liu
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Linlin Hu.

Ethics declarations

Funding

This study was funded by Jiangsu Vcare PharmaTech-Co. Ltd, the National Natural Science Foundation of China (No. 81503340), the National Natural Science Foundation of Jiangsu Province (No. BK20150645), Shijiazhuang Pharmaceutical Foundation of Jiangsu Pharmaceutical Association (No. SY202306-4), and the CHIA TAI TIAQING Pharmaceutical Foundation of Jiangsu Pharmaceutical Association (No. Q202203).

Conflict of Interest

Yong Wu and Yongqiang Liu are employees of Jiangsu Vcare PharmaTech Co., Ltd., Nanjing, China. All other authors have indicated that they have no conflicts of interest regarding the content of this article.

Ethics Approval

The study protocol was approved (approval number, 2022ZDSYLL245-Y0 and 2022ZDSYLL245-P01) by the Ethics Committee of the Zhongda Hospital, Medical School, Southeast University (Nanjing, China) on 22 August 2022 and 25 August 2022, respectively.

Informed Consent

Written informed consent was obtained from all individual participants prior to their enrolment.

Availability of Data and Materials

All data generated in this study are available from the corresponding author upon reasonable request.

Code Availability

Not applicable.

Consent to Publish

Not applicable.

Authors Contributions

LH and HW contributed to the study conception and design. LH, M-mC, WQ, LT, QyS, and TD contributed to the material preparation, data collection, and analysis. YW and YL contributed to the new reagents for the bioanalysis. The first draft of the manuscript was written by LH and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 173 KB) (download PDF )

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hu, L., Sun, Q., Tang, L. et al. Food Effect on the Pharmacokinetics of VC004, a Tropomyosin Receptor Kinase Inhibitor: A Randomized Crossover Trial in Healthy Chinese Subjects. Clin Drug Investig 44, 79–85 (2024). https://doi.org/10.1007/s40261-023-01334-y

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1007/s40261-023-01334-y