Skip to main content
SpringerLink
Log in

Pharmacokinetics of Selinexor: The First-in-Class Selective Inhibitor of Nuclear Export

  • Review Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

The functionality of many tumor suppressor proteins (TSPs) and oncoprotein transcript RNAs largely depend on their location within the cell. The exportin 1 complex (XPO1) transports many of these molecules from the nucleus into the cytoplasm, thereby inactivating TSPs and activating oncoprotein transcript RNAs. Aberrations of these molecules or XPO1 can increase this translocation process, leading to oncogenesis. Selinexor is a selective inhibitor of nuclear export and is an active agent in various malignancies. It is currently approved for relapsed or refractory diffuse large B-cell lymphoma as well as multiple myeloma. Following oral administration, selinexor exhibits linear and time-independent pharmacokinetics (PK) across a wide dose range, with moderately rapid absorption (time to reach maximum concentration [Tmax] 2–4 h) and moderate elimination (half-life [t½] 6–8 h). Selinexor PK observed among patients with various solid tumors and hematologic malignancies is consistent irrespective of disease. Population PK analyses demonstrated the PK of selinexor is well-described by a two-compartment model, with significant relationships for body weight on apparent clearance and apparent central volume of distribution, and sex on apparent clearance, which result in clinically non-relevant changes in exposure. These analyses also suggested selinexor PK are not significantly impacted by various concomitant medications and organ dysfunction (hepatic/renal). The time course of selinexor PK appears similar between pediatric and adult patients, although higher exposures have been observed among pediatric patients relative to adults administered similar milligrams per meter squared (mg/m2) doses of selinexor.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

References

  1. Kau TR, Way JC, Silver PA. Nuclear transport and cancer: from mechanism to intervention. Nat Rev Cancer. 2004;4:106–17.

    Article  CAS  Google Scholar 

  2. Senapedis WT, Baloglu E, Landesman Y. Clinical translation of nuclear export inhibitors in cancer. Semin Cancer Biol. 2014;27:74–86.

    Article  CAS  Google Scholar 

  3. Jans DA, Martin AJ, Wagstaff KM. Inhibitors of nuclear transport. Curr Opin Cell Biol. 2019;58:50–60.

    Article  CAS  Google Scholar 

  4. Tan DS, Bedard PL, Kuruvilla J, Siu LL, Razak ARA. Promising SINEs for embargoing nuclear-cytoplasmic export as an anticancer strategy. Cancer Discov. 2014;4:527–37.

    Article  CAS  Google Scholar 

  5. Abdul Razak AR, Maru-Soerensen M, Gabrail NY, Gerecitano JF, Shields AF, Unger TJ, et al. First-in-class, first-in-human phase I study of selinexor, a selective inhibitor of nuclear export, in patients with advanced solid tumors. J Clin Oncol. 2016;34:4142–50.

    Article  CAS  Google Scholar 

  6. Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ, Huff CA, et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381:727–38.

    Article  CAS  Google Scholar 

  7. Grosicki S, Simonova M, Spicka I, Pour L, Kriachok I, Gavriatopoulou M, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. 2020;396:1563–73.

    Article  CAS  Google Scholar 

  8. Therapeutics K. XPOVIO (selinexor): highlights of prescribing information. Newton: Karyopharm Therapeutics; 2020.

    Google Scholar 

  9. Nagesh K, Maerevoet M, Cavallo F, Follows G, Goy A, Vermaat JSP, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Hematol. 2020;7:e511–22.

    Article  Google Scholar 

  10. Karyopharm Therapeutics. Data on file.

  11. Azmi AS, Al-Katib A, Aboukameel A, McCauley D, Kauffman M, Shacham S, Mohammad RM. Selective inhibitors of nuclear export for the treatment of non-Hodgkin’s lymphomas. Haematology. 2013;98(7):1098–106.

    Article  CAS  Google Scholar 

  12. London CA, Bernabe LF, Barnard S, Kisseberth WC, Borgatti A, Henson M, et al. Preclinical evaluation of the novel, orally bioavailable selective inhibitor of nuclear export (SINE) KPT-335 in spontaneous canine cancer: results of a Phase I study. PLoS ONE. 2014;9(2):e87585.

    Article  Google Scholar 

  13. Han X, Wang J, Shen Y, Zhang N, Wang S, Yao J, Shi Y. CRM1 as a new therapeutic target for non-Hodgkin lymphoma. Leuk Res. 2015;39(1):38–46.

    Article  CAS  Google Scholar 

  14. Crespo M, Carabia J, Jiménez I, Bobillo S, Abrisqueta P, Palacio C, et al. Xpo-1 inhibition synergizes with BCR inhibition, blocks tumor growth and tumor-associated macrophages infiltration and prolongs survival in a bioluminescent animal model of primary central nervous system lymphoma. Blood. 2017;130:2808–2808.

    Article  Google Scholar 

  15. Schmidt J, Braggio E, Kortuem KM, Egan JB, Zhu YX, Xin CS, et al. Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276. Leukemia. 2013;27(12):2357–65.

    Article  CAS  Google Scholar 

  16. Tai YT, Landesman Y, Acharya C, Calle Y, Zhong MY, Cea M, et al. CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications. Leukemia. 2014;28(1):155–65.

    Article  CAS  Google Scholar 

  17. Li S, Fu J, Lu C, Mapara MY, Raza S, Hengst U, Lentzsch S. Elevated translation initiation factor eIF4E is an attractive therapeutic target in multiple myeloma. Mol Cancer Ther. 2016;15(4):711–9.

    Article  Google Scholar 

  18. Culjkovic-Kraljacic B, Baguet A, Volpon L, Amri A, Borden KLB. The oncogene eIF4E reprograms the nuclear pore complex to promote mRNA export and oncogenic transformation. Cell Rep. 2012;2(2):207–15.

    Article  CAS  Google Scholar 

  19. Culjkovic B, Topisirovic I, Skrabanek L, Ruiz-Gutierrez M, Borden KLB. eIF4E is a central node of an RNA regulon that governs cellular proliferation. J Cell Biol. 2006;175(3):415–26.

    Article  CAS  Google Scholar 

  20. Volpon L, Culjkovic-Kraljacic B, Sohn HS, Blanchet-Cohen A, Osborne MJ, Borden KLB. A biochemical framework for eIF4E-dependent mRNA export and nuclear recycling of the export machinery. RNA. 2017;23:927–37.

    Article  CAS  Google Scholar 

  21. Kashyap T, Crochiere M, Friedlander S, Klebanov B, Senapedis W, Baloglu E, et al. Selective inhibitors of nuclear export (SINE) block the expression of DNA damage repair proteins and sensitize cancer cells to DNA damage therapeutic agents. Eur J Cancer. 2014;50:83 (Poster 247).

    Article  Google Scholar 

  22. Kashyap T, Argueta C, Unger T, Klebanov B, Debler S, Senapedis W, et al. Selinexor reduces the expression of DNA damage repair proteins and sensitizes cancer cells to DNA damaging agents. Oncotarget. 2018;9(56):30773–86.

    Article  Google Scholar 

  23. Rashal T, McCauley D, Ilouze M, Raphael N, Solomonik I, et al. Abstract 2075: combination tTerapy KPT-SINE (selective inhibitors of nuclear export) with radiotherapy have additive effects in non-small cell lung cancer (NSCLC) cells in vitro and in vivo. In: Cancer Res. 2013;73(8 Suppl): AACR 104th annual meeting; 6–10 Apr 2013; Washington, DC.

  24. Ferreiro-Neira I, Torres NE, Liesenfeld LF, Chan CH, Penson T, Landesman Y, et al. XPO1 inhibition enhances radiation response in preclinical models of rectal cancer. Clin Cancer Res. 2016;22:1663–73.

    Article  CAS  Google Scholar 

  25. Wahba A, Rath BH, O’Neill JW, Camphausen K, Tofilon PJ. The XPO1 inhibitor selinexor inhibits translation and enhances the radiosensitivity of glioblastoma cells grown in vitro and in vivo. Mol Cancer Ther. 2018;17(8):1717–26.

    Article  CAS  Google Scholar 

  26. Argueta C, Kashyap T, Klebanov B, Unger TJ, Guo C, Harrington S, et al. Selinexor synergizes with dexamethasone to repress mTORC1 signaling and induce multiple myeloma cell death. Oncotarget. 2018;9:25529–44.

    Article  Google Scholar 

  27. Kuruvilla J, Savona M, Baz R, Mau-Sorensen PM, Gabrail N, Garzon R, et al. Selective inhibition of nuclear export with selinexor in patients with non-Hodgkin lymphoma. Blood. 2017;129:3175–83.

    Article  CAS  Google Scholar 

  28. Gounder MM, Zer A, Tap WD, Salah S, Dickson MA, Gupta AA, et al. Phase IB study of selinexor, a first-in-class inhibitor of nuclear export, in patients with advanced refractory bone of soft tissue sarcoma. J Clin Oncol. 2016;34:3166–74.

    Article  CAS  Google Scholar 

  29. Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, Forgue ST. Confidence interval criteria for assessment of dose proportionality. Pharma Res. 2000;17(10):1278–83.

    Article  CAS  Google Scholar 

  30. Xu H, Li H, Wada R, Bader JC, Tang S, Shah J, Shacham S. Selinexor population pharmacokinetic and exposure-response analyses to support dose optimization in patients with diffuse large B-cell lymphoma. Cancer Chemother Pharmacol. 2021. https://doi.org/10.1007/s00280-021-04258-6

    Article  PubMed  PubMed Central  Google Scholar 

  31. Alexander TB, Lacayo NJ, Choi JK, Ribeiro RC, Pui CH, Rubnitz JE. Phase I study of selinexor, a selective inhibitor of nuclear export, in combination with fludarabine and cytarabine, in pediatric relapsed or refractory acute leukemia. J Clin Oncol. 2016;34:409–4101.

    Article  Google Scholar 

  32. Prentice TC, Siri W, Berlin NI, Hyde GM, Parsons RJ, Joiner EE, Lawrence JH. Studies of total body water with tritium. J Clinical Investig. 1952;31(4):412–8.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Karyopharm Therapeutics, 85 Wells Ave, Newton, MA, 02459, USA

    Justin C. Bader, Sharon Shacham & Hongmei Xu

  2. Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada

    Albiruni R. Abdul Razak

Authors
  1. Justin C. Bader
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Albiruni R. Abdul Razak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sharon Shacham
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hongmei Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hongmei Xu.

Ethics declarations

Funding

No external funds were used in the preparation of this manuscript.

Conflicts of Interest

Justin C. Bader and Hongmei Xu are full-time employees of Karyopharm Therapeutics and own stock/stock options in the company. Sharon Shacham is Chief Scientific Officer of Karyopharm Therapeutics and owns stock/stock options in the company. Albiruni R. Abdul Razak is full-time employee of Princess Margaret Cancer Centre, Toronto, and has received research funding from Karyopharm Therapeutics.

Ethics approval

The Institutional Review Boards or Independent Ethics Committees of all investigational sites approved all Clinical Studies and all studies were performed in accordance with the Declaration of Helsinki and Good Clinical Practice.

Consent to participate

All study participants provided consent form for study participation.

Consent for publication

I have signed the license agreement for publication.

Availability of data and material

Not applicable.

Code availability

Not applicable.

Author Contributions

All authors have contributed to the preparation and review of this manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bader, J.C., Abdul Razak, A.R., Shacham, S. et al. Pharmacokinetics of Selinexor: The First-in-Class Selective Inhibitor of Nuclear Export. Clin Pharmacokinet 60, 957–969 (2021). https://doi.org/10.1007/s40262-021-01016-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-021-01016-y

Search

Navigation