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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.

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.

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  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    PRA Magyarország Kft, Fázis I-es Klinikai Farmakológiai Vizsgálóhely, Budapest, Hungary.

    ,

    Roche Innovation Center of New York, New York, NY, USA.

    ,

    Roche Innovation Center of New York, New York, NY, USA.

    ,

    Roche Innovation Center of New York, New York, NY, USA.

    ,

    Roche Innovation Center of New York, New York, NY, USA.

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    York Bioanalytical Solutions, Sandwich, UK.

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    Roche Innovation Center of Basel, Basel, Switzerland.

    Roche Innovation Center of New York, New York, NY, USA. jianguo.zhi8@gmail.com.

    Source

    Cancer chemotherapy and pharmacology 84:1 2019 Jul pg 93-103

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31062077

    Citation

    Pápai, Zsuzsanna, et al. "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." Cancer Chemotherapy and Pharmacology, vol. 84, no. 1, 2019, pp. 93-103.
    Pápai Z, Chen LC, Da Costa D, et al. 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. Cancer Chemother Pharmacol. 2019;84(1):93-103.
    Pápai, Z., Chen, L. C., Da Costa, D., Blotner, S., Vazvaei, F., Gleave, M., ... Zhi, J. (2019). 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. Cancer Chemotherapy and Pharmacology, 84(1), pp. 93-103. doi:10.1007/s00280-019-03851-0.
    Pápai Z, et al. 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. Cancer Chemother Pharmacol. 2019;84(1):93-103. PubMed PMID: 31062077.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - 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. AU - Pápai,Zsuzsanna, AU - Chen,Lin-Chi, AU - Da Costa,Daniel, AU - Blotner,Steven, AU - Vazvaei,Faye, AU - Gleave,Michelle, AU - Jones,Russell, AU - Zhi,Jianguo, Y1 - 2019/05/06/ PY - 2018/11/08/received PY - 2019/04/25/accepted PY - 2019/5/8/pubmed PY - 2019/5/8/medline PY - 2019/5/8/entrez KW - Absolute bioavailability KW - Idasanutlin KW - MDM2 antagonist KW - Mass balance KW - Metabolic profiling SP - 93 EP - 103 JF - Cancer chemotherapy and pharmacology JO - Cancer Chemother. Pharmacol. VL - 84 IS - 1 N2 - 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. SN - 1432-0843 UR - https://www.unboundmedicine.com/medline/citation/31062077/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 L2 - https://dx.doi.org/10.1007/s00280-019-03851-0 DB - PRIME DP - Unbound Medicine ER -