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A phase I, open-label, multicenter study to evaluate the pharmacokinetics and safety of oral panobinostat in patients with advanced solid tumors and varying degrees of renal function

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Abstract

Purpose

This study assessed the pharmacokinetics and safety of oral panobinostat and its metabolite BJB432 in patients with advanced solid tumors and normal to severely impaired renal function.

Methods

Patients with varying degrees of renal impairment, defined by their 24-h baseline urine creatinine clearance (as normal, mild, moderate or severe), received a single oral dose of 30 mg panobinostat. Serial plasma samples were collected pre-dose and up to 96-h post-dose. Serial urine samples were collected for 24-h post-dose. Following the serial PK sampling, patients received 30 mg oral panobinostat thrice weekly for as long as the patient had benefit. Pharmacokinetic parameters were derived using non-compartmental analysis.

Results

Thirty-seven patients were enrolled, and median age was 64 (range 40–81) years. Eleven patients had normal renal function; 10, 10, and 6 patients had mild, moderate, and severe renal impairment, respectively. Geometric means of AUC0–∞ in the normal, mild, moderate, and severe groups were 224.5, 144.3, 223.1, and 131.7 ng h/mL, respectively. Geometric mean ratio of BJB432 to parent drug plasma AUC0–∞ was 0.64 in the normal group and increased to 0.81, 1.13, and 1.20 in the mild, moderate, and severe groups, respectively. The fraction excreted as unchanged panobinostat was small (<2 %), with a large variability. The renal clearance of panobinostat and tolerability was similar across all four groups.

Conclusion

Systemic exposure to panobinostat did not increase with severity of renal impairment, and the drug was tolerated equally; thus, patients with renal impairment do not require starting dose adjustments.

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Ethical standard

The study was performed in accordance with ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The protocol was approved by the institutional review board at each participating institution. All patients provided written informed consent. The study is registered at www.clinicaltrials.gov with the identifier NCT00997399.

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Authors and Affiliations

  1. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    Sunil Sharma

  2. Department of Medical Oncology, University Medical Center, Utrecht, The Netherlands

    Petronella O. Witteveen & Martijn P. Lolkema

  3. Kantonsspital St. Gallen, Klinik für Onkologie und Hämatologie, St. Gallen, Switzerland

    Dagmar Hess

  4. Department of Clinical Oncology, K1-P, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands

    Hans Gelderblom

  5. The Clatterbridge Cancer Centre NHS, Bebington, Wirral, University of Liverpool, Liverpool, UK

    Syed A. Hussain

  6. Novartis Pharma AG, Basel, Switzerland

    Maria G. Porro & Edward Waldron

  7. Novartis Pharmaceutical Corporation, East Hanover, NJ, USA

    Sue-zette Valera & Song Mu

Authors
  1. Sunil Sharma
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  2. Petronella O. Witteveen
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  3. Martijn P. Lolkema
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  4. Dagmar Hess
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  5. Hans Gelderblom
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  6. Syed A. Hussain
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  7. Maria G. Porro
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  8. Edward Waldron
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  9. Sue-zette Valera
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  10. Song Mu
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Corresponding author

Correspondence to Hans Gelderblom.

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Sharma, S., Witteveen, P.O., Lolkema, M.P. et al. A phase I, open-label, multicenter study to evaluate the pharmacokinetics and safety of oral panobinostat in patients with advanced solid tumors and varying degrees of renal function. Cancer Chemother Pharmacol 75, 87–95 (2015). https://doi.org/10.1007/s00280-014-2612-8

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  • DOI: https://doi.org/10.1007/s00280-014-2612-8

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