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

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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.

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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.

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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
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  2. Cindy Q. Xia
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  3. Bingli Ma
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  5. Wen C. Shyu
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  6. Suresh K. Balani
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Corresponding author

Correspondence to Suresh K. Balani.

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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.

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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

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

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