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Cancer Chemotherapy and Pharmacology

, Volume 84, Issue 1, pp 93–103 | Cite as

A single-center, open-label study investigating the excretion balance, pharmacokinetics, metabolism, and absolute bioavailability of a single oral dose of [14C]-labeled idasanutlin and an intravenous tracer dose of [13C]-labeled idasanutlin in a single cohort of patients with solid tumors

  • Zsuzsanna Pápai
  • Lin-Chi Chen
  • Daniel Da Costa
  • Steven Blotner
  • Faye Vazvaei
  • Michelle Gleave
  • Russell Jones
  • Jianguo ZhiEmail author
Original Article

Abstract

Purpose

Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic p53 activator with oral administration. To determine the need to conduct dedicated trial(s) for organ impairment on pharmacokinetic (PK) exposure and/or drug–drug interactions, a single dose of [14C]- and [13C]-labeled idasanutlin was evaluated.

Methods

This study was an open-label, non-randomized, single-center trial of idasanutlin to investigate the excretion balance, pharmacokinetics, metabolism, and absolute bioavailability of a single oral dose of [14C]-labeled idasanutlin and an IV tracer dose of [13C]-labeled idasanutlin in a single cohort of patients with solid tumors. After completing cycle 1 assessments, patients could have participated in an optional treatment extension of idasanutlin. Clinical endpoints were PK, and safety/tolerability.

Results

Co-administration of an oral dose of idasanutlin with an IV tracer dose revealed low systemic CL, a moderate Vd, and a moderate (40.1%) absolute bioavailability of idasanutlin. Idasanutlin and its major inactive metabolite, M4, were the major circulating moieties in plasma, and excretion of idasanutlin-associated radioactivity was primarily via the fecal route (91.5% of the dose), with negligible amounts recovered in urine, following oral administration.

Conclusion

The clinical implications of this study support the conclusion that renal impairment is unlikely to significantly impact exposure to idasanutlin and M4 metabolite, whereas a significant hepatic impairment may potentially alter exposure to the parent drug and/or metabolite(s). The potential for drug–drug interactions is low.

Keywords

Idasanutlin MDM2 antagonist Mass balance Absolute bioavailability Metabolic profiling 

Notes

Acknowledgements

The authors would like to acknowledge key contributions from Roche colleagues, investigational site staff, and patient volunteers.

Funding

The study was sponsored by F. Hoffmann-La Roche. The funding sources had no role in the design, analysis, and interpretation of the results, and thus the authors were independent from the funding source.

Compliance with ethical standards

Conflict of interest

LC, SB, FV, RJ, and JZ are employees of Roche. DD was an employee of Rutgers University, through a fellowship grant from Roche.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Zsuzsanna Pápai
    • 1
  • Lin-Chi Chen
    • 2
  • Daniel Da Costa
    • 2
  • Steven Blotner
    • 2
  • Faye Vazvaei
    • 2
  • Michelle Gleave
    • 3
  • Russell Jones
    • 4
  • Jianguo Zhi
    • 2
    Email author
  1. 1.PRA Magyarország Kft, Fázis I-es Klinikai Farmakológiai VizsgálóhelyBudapestHungary
  2. 2.Roche Innovation Center of New YorkNew YorkUSA
  3. 3.York Bioanalytical SolutionsSandwichUK
  4. 4.Roche Innovation Center of BaselBaselSwitzerland

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