Preclinical PK/PD model for the combinatorial use of dexamethasone and sulpiride in the treatment of breast cancer

Abstract

Previous studies show that dopamine D2-like receptor (D2DR) antagonist sulpiride (SUL) enhances the antitumor efficacy of dexamethasone (DEX) in drug-resistant breast cancer involving cancer stem-like cells (CSCs). In this study, we investigated the pharmacokinetic (PK) properties of SUL in nude mice and developed a semi-mechanism PK/PD model to quantitatively characterize the synergistic effect of DEX and SUL in preclinical breast cancer xenografts. After nude mice received oral administration of a single dose of SUL (50 mg/kg, ig), plasma concentrations were assessed using LC-MS/MS. A two-compartment model with double first-order absorption rate was developed to describe the PK profiles of SUL. The pharmacodynamic (PD) study was conducted in nude mice bearing human breast cancer MCF-7/Adr xenografts, which received oral administration of DEX (1, 8 mg·kg−1·d−1) or SUL (25, 50 mg·kg−1·d−1) alone or in various combination. Tumor volumes were measured every other day. The PK model of SUL as well as that of DEX with a time-dependent clearance were integrated into the final PK/PD model both using Hill’s function, where DEX exerted its antitumor efficacy by inhibiting the proliferation of tumor cells, and SUL enhanced DEX responses by decreasing the sensitivity parameter EC50. The PK/PD model was evaluated and subjected external validation. Finally, simulations were performed to predict the antitumor efficacy of DEX combined with SUL under various dose regimens, where changing dosing frequency of SUL had little effect, while the antitumor efficacy was predicted to be improved when DEX was given more frequently. The established PK/PD model in this study quantitatively characterizes the antitumor efficacy of the DEX combined with SUL as well as their synergism, and the simulations could provide reference for dose optimization of the combination in future studies.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.

  2. 2.

    Gradishar WJ, Anderson BO, Balassanian R, Blair SL, Burstein HJ, Cyr A, et al. Invasive Breast Cancer Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2016;14:324–54. (PMID: 26957618).

  3. 3.

    Waks AG, Winer EP. Breast cancer treatment: a review. JAMA. 2019;321:288–300.

  4. 4.

    Gu G, Dustin D, Fuqua SA. Targeted therapy for breast cancer and molecular mechanisms of resistance to treatment. Curr Opin Pharm. 2016;31:97–103.

  5. 5.

    Bai X, Ni J, Beretov J, Graham P, Li Y. Cancer stem cell in breast cancer therapeutic resistance. Cancer Treat Rev. 2018;69:152–63.

  6. 6.

    Gong H, Jarzynka MJ, Cole TJ, Lee JH, Wada T, Zhang B, et al. Glucocorticoids antagonize estrogens by glucocorticoid receptor-mediated activation of estrogen sulfotransferase. Cancer Res. 2008;68:7386–93.

  7. 7.

    Yuan Y, Zhou X, Ren Y, Zhou S, Wang L, Ji S, et al. Semi-mechanism-based pharmacokinetic/pharmacodynamic model for the combination use of dexamethasone and gemcitabine in breast cancer. J Pharm Sci. 2015;104:4399–408.

  8. 8.

    Wang LJ, Li J, Hao FR, Yuan Y, Li JY, Lu W, et al. Dexamethasone suppresses the growth of human non-small cell lung cancer via inducing estrogen sulfotransferase and inactivating estrogen. Acta Pharm Sin. 2016;37:845–56.

  9. 9.

    Egberts JH, Schniewind B, Patzold M, Kettler B, Tepel J, Kalthoff H, et al. Dexamethasone reduces tumor recurrence and metastasis after pancreatic tumor resection in SCID mice. Cancer Biol Ther. 2008;7:1044–50.

  10. 10.

    Li J, Chen R, Yao QY, Liu SJ, Tian XY, Hao CY, et al. Time-dependent pharmacokinetics of dexamethasone and its efficacy in human breast cancer xenograft mice: a semi-mechanism-based pharmacokinetic/pharmacodynamic model. Acta Pharm Sin. 2018;39:472–81.

  11. 11.

    Castro-Caldas M, Mendes AF, Carvalho AP, Duarte CB, Lopes MC. Dexamethasone prevents interleukin-1beta-induced nuclear factor-kappaB activation by upregulating IkappaB-alpha synthesis, in lymphoblastic cells. Mediat Inflamm. 2003;12:37–46.

  12. 12.

    Yano A, Fujii Y, Iwai A, Kageyama Y, Kihara K. Glucocorticoids suppress tumor angiogenesis and in vivo growth of prostate cancer cells. Clin Cancer Res. 2006;12:3003–9.

  13. 13.

    Ablett MP, Singh JK, Clarke RB. Stem cells in breast tumours: are they ready for the clinic? Eur J Cancer. 2012;48:2104–16.

  14. 14.

    Zhao J. Cancer stem cells and chemoresistance: the smartest survives the raid. Pharm Ther. 2016;160:145–58.

  15. 15.

    Wang S, Mou Z, Ma Y, Li J, Li J, Ji X, et al. Dopamine enhances the response of sunitinib in the treatment of drug-resistant breast cancer: Involvement of eradicating cancer stem-like cells. Biochem Pharm. 2015;95:98–109.

  16. 16.

    Sachlos E, Risueno RM, Laronde S, Shapovalova Z, Lee JH, Russell J, et al. Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells. Cell. 2012;149:1284–97.

  17. 17.

    Yeh CT, Wu AT, Chang PM, Chen KY, Yang CN, Yang SC, et al. Trifluoperazine, an antipsychotic agent, inhibits cancer stem cell growth and overcomes drug resistance of lung cancer. Am J Respir Crit Care Med. 2012;186:1180–8.

  18. 18.

    Rzewuska M. [Sulpiride: the best known atypical, safe neuroleptic drug. Review of literature]. Psychiatr Pol. 1998;32:655–66.

  19. 19.

    Li J, Yao QY, Xue JS, Wang LJ, Yuan Y, Tian XY, et al. Dopamine D2 receptor antagonist sulpiride enhances dexamethasone responses in the treatment of drug-resistant and metastatic breast cancer. Acta Pharm Sin. 2017;38:1282–96.

  20. 20.

    Iwanaga K, Honjo T, Miyazaki M, Kakemi M. Time-dependent changes in hepatic and intestinal induction of cytochrome P450 3A after administration of dexamethasone to rats. Xenobiotica. 2013;43:765–73.

  21. 21.

    Watanabe K, Sawano T, Jinriki T, Sato J. Studies on intestinal absorption of sulpiride (3): intestinal absorption of sulpiride in rats. Biol Pharm Bull. 2004;27:77–81.

  22. 22.

    Koch G, Walz A, Lahu G, Schropp J. Modeling of tumor growth and anticancer effects of combination therapy. J Pharm Pharm. 2009;36:179–97.

  23. 23.

    Helmy SA. Therapeutic drug monitoring and pharmacokinetic compartmental analysis of sulpiride double-peak absorption profile after oral administration to human volunteers. Biopharm Drug Dispos. 2013;34:288–301.

  24. 24.

    Leggas M, Kuo KL, Robert F, Cloud G, deShazo M, Zhang R, et al. Intensive anti-inflammatory therapy with dexamethasone in patients with non-small cell lung cancer: effect on chemotherapy toxicity and efficacy. Cancer Chemother Pharm. 2009;63:731–43.

  25. 25.

    Lim CN, Salem AH. A semi-mechanistic integrated pharmacokinetic/pharmacodynamic model of the testosterone effects of the gonadotropin-releasing hormone agonist leuprolide in prostate cancer patients. Clin Pharm. 2015;54:963–73.

  26. 26.

    Romero E, Velez de Mendizabal N, Cendros JM, Peraire C, Bascompta E, Obach R, et al. Pharmacokinetic/pharmacodynamic model of the testosterone effects of triptorelin administered in sustained release formulations in patients with prostate cancer. J Pharm Exp Ther. 2012;342:788–98.

  27. 27.

    Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharm Rev. 2011;63:182–217.

  28. 28.

    Missale C, Nash SR, Robinson SW, Jaber M, Caron MG. Dopamine receptors: from structure to function. Physiol Rev. 1998;78:189–225.

  29. 29.

    Hao F, Wang S, Zhu X, Xue J, Li J, Wang L, et al. Pharmacokinetic-pharmacodynamic modeling of the anti-tumor effect of sunitinib combined with dopamine in the human non-small cell lung cancer xenograft. Pharm Res. 2017;34:408–18.

  30. 30.

    Ma YH, Wang SY, Ren YP, Li J, Guo TJ, Lu W, et al. Antitumor effect of axitinib combined with dopamine and PK-PD modeling in the treatment of human breast cancer xenograft. Acta Pharm Sin. 2019;40:243–56.

  31. 31.

    Bhatt-Mehta V, Nahata MC. Dopamine and dobutamine in pediatric therapy. Pharmacotherapy. 1989;9:303–14.

  32. 32.

    O’Connor SE, Brown RA. The pharmacology of sulpiride-a dopamine receptor antagonist. Gen Pharm. 1982;13:185–93.

  33. 33.

    Dasta JF, Kirby MG. Pharmacology and therapeutic use of low-dose dopamine. Pharmacotherapy. 1986;6:304–10.

Download references

Acknowledgements

The study was supported by the National Natural Science Foundation of China (NSFC) (Grant No. 81673500). The first two authors are supported by Pfizer Sponsorships for Pharmacometrics.

Author information

TYZ, WL, and JL designed research; JL, QYY, YY, JSX,  and WJC  performed research; JL, QYY,  and RC analyzed the data; QYY and TYZ organized the manuscript.

Correspondence to Tian-yan Zhou.

Ethics declarations

Competing interests

The authors declare no competing interest.

Supplementary information

Supplementary tables

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Keywords

  • breast cancer
  • dexamethasone
  • sulpiride
  • pharmacokinetic/pharmacodynamic model
  • synergistic effect