Skip to main content

Advertisement

Springer Nature Link
Log in

CYP Suppression in Human Hepatocytes by Monomethyl Auristatin E, the Payload in Brentuximab Vedotin (Adcetris®), is Associated with Microtubule Disruption

  • Original Research Article
  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objectives

Monomethyl auristatin E (MMAE), the toxin linked to CD30-specific monoclonal antibody of Adcetris® (brentuximab vedotin), is a potent anti-microtubule agent. Brentuximab vedotin has been approved for the treatment of relapsed or refractory Hodgkin lymphoma and anaplastic large cell lymphoma. Cytochrome P450 (CYP) induction assessment of MMAE was conducted in human hepatocytes to assess DDI potentials and its translation to clinic.

Methods

MMAE was incubated at 1–1000 nM with cultured primary human hepatocytes for 72 h, and CYP1A2, CYP2B6, and CYP3A4 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction and CYP-specific probe substrate by liquid chromatography coupled with mass spectrometry, along with microtubule disruption by immunofluorescence staining using anti-β-tubulin antibody and imaging.

Results

MMAE up to 10 nM had no significant effect on CYP1A2, CYP2B6, and CYP3A4 mRNA expression and activity, whereas at higher concentrations of 100- and 1000-nM MMAE, the CYP mRNA expression and activity were diminished substantially. Further investigation showed that the degree of CYP suppression was paralleled by that of microtubule disruption by MMAE, as measured by increase in the number of β-tubulin-positive aggregates. At the clinical dose, the concentration of MMAE was 7 nM which did not show any significant CYP suppression or microtubule disruption in hepatocytes.

Conclusions

MMAE was not a CYP inducer in human hepatocytes. However, it caused a concentration-dependent CYP mRNA suppression and activity. The CYP suppression was associated with microtubule disruption, supporting the reports that intact microtubule architecture is required for CYP regulations. The absence of CYP suppression and microtubule disruption in vitro at the clinical plasma concentrations of MMAE (< 10 nM) explains the lack of pharmacokinetic drug interaction between brentuximab vedotin and midazolam, a sensitive CYP3A substrate, reported in patients.

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+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

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

References

  1. Tolcher AW. Antibody drug conjugates: lessons from 20 years of clinical experience. Ann Oncol. 2016;27:2168–72.

    Article  PubMed  CAS  Google Scholar 

  2. Reichert JM. Antibodies to watch in 2017. mAbs. 2017;9:167–81.

    Article  PubMed  CAS  Google Scholar 

  3. Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, Larson RA, Erba HP, Stiff PJ, Stuart RK, Walter RB, Tallman MS, Stenke L, Appelbaum FR. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013;121:4854–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Van de Donk NWCJ, Dhimolea E. Brentuximab vedotin. mAbs. 2012;4:458–65.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Madan A, Dehaan R, Mudra D, Carroll K, LeCluyse E, Parkinson A. Effect of cryopreservation on cytochrome P-450 enzyme induction in cultured rat hepatocytes. Drug Metab Dispos. 1999;27:327–35.

    PubMed  CAS  Google Scholar 

  6. Schneider CA, Rasband WS, Eliceiri KW. NIH image to imageJ: 25 years of image analysis. Nat Methods. 2012;9:671–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Han TH, Gopal AK, Ramchandren R, Goy A, Chen R, Matous JV, Cooper M, Grove LE, Alley SC, Lynch CM, O’Connor OA. CYP3A-mediated drug–drug interaction potential and excretion of Brentuximab Vedotin, an antibody–drug conjugate, in patients with CD30-positive hematologic malignancies J. Clin Pharm. 2013;53:866–77.

    Article  Google Scholar 

  8. Hariprasad N, Ramsden D, Palamanda J, Dekeyser JG, Fahmi OA, Kenny JR, Einolf H, Mohutsky M, Pardon M, Siu AY, Chen L, Sinz M, Jones B, Walsky R, Dallas S, Balani SK, LeCluyse E, Zhang G, Buckley D, and Tweedie D. Considerations from the IQ induction working group in response to drug–drug interaction guidances from regulatory agencies: focus on down-regulation, CYP2C induction and CYP2B6 positive control. Drug Metab Dispos. 2017;45:1049-59.

    Article  CAS  Google Scholar 

  9. Dvorak Z, Modriansky M, Pichard-Garcia L, Balaguer P, Vilarem M-J, Ulrichova J, Maurel P, Pascussi J-M. Colchicine down-regulates cytochrome P450 2B6, 2C8, 2C9 and 3A4 in human hepatocytes by affecting their glucocorticoid receptor-mediated regulation. Mol Pharmacol. 2003;64:160–9.

    Article  PubMed  CAS  Google Scholar 

  10. Dvorak Z, Ulrichova J, Modriansky M. Role of microtubules network in CYP genes expression. Curr Drug Metab. 2005;6:545–52.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Sekisui XenoTech, LLC for work with CYP induction study, Steve Alley of Seattle Genetics, and Adedigbo Fasanmade of Takeda for the helpful discussions.

Funding

No funding source to declare.

Author information

Authors and Affiliations

  1. Drug Safety Research and Evaluation, Takeda Pharmaceuticals International Co., Cambridge, MA, USA

    Francis S. Wolenski

  2. Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., 35 Landsdowne Street, Cambridge, MA, USA

    Cindy Q. Xia, Bingli Ma, Wen C. Shyu & Suresh K. Balani

  3. Seattle Genetics Inc., Bothell, WA, USA

    Tae H. Han

Authors
  1. Francis S. Wolenski
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Cindy Q. Xia
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Bingli Ma
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Tae H. Han
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Wen C. Shyu
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Suresh K. Balani
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Suresh K. Balani.

Ethics declarations

Conflict of interest

All authors were compensated employees of either Seattle Genetics, Inc. (THH) or Takeda Pharmaceuticals International Co. (FSW, BM, CQX, WCS, and SKB) when this research was conducted.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wolenski, F.S., Xia, C.Q., Ma, B. et al. CYP Suppression in Human Hepatocytes by Monomethyl Auristatin E, the Payload in Brentuximab Vedotin (Adcetris®), is Associated with Microtubule Disruption. Eur J Drug Metab Pharmacokinet 43, 347–354 (2018). https://doi.org/10.1007/s13318-017-0455-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13318-017-0455-5