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Evaluation of pharmacokinetics and safety of ponatinib in subjects with chronic hepatic impairment and matched healthy subjects

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Abstract

Purpose

This study evaluated the effects of chronic hepatic impairment on the single-dose pharmacokinetics (PK) of the tyrosine kinase inhibitor ponatinib.

Methods

Subjects (n = 16) had Child-Pugh class A (mild, n = 6), B (moderate, n = 6), or C (severe, n = 4) hepatic impairment and were matched with healthy controls (n = 8). Each subject received a single oral dose of ponatinib 30 mg under fasting conditions, and PK parameters were assessed in blood samples collected through 96 h post-dose.

Results

Ponatinib maximum plasma concentrations (C max) were observed after 5–6 h in Child-Pugh A, Child-Pugh B, and healthy subjects, and after ~3 h in Child-Pugh C subjects. The estimated  % geometric mean ratios for C max, area under the plasma concentration–time curves from time zero to last observation (AUC0–t ) and to infinity (AUC0–∞) suggested a slightly lower exposure in Child-Pugh B (61.4, 89.1, and 90.6 %, respectively) and Child-Pugh C subjects (62.8, 77.1, and 79.4 %) versus healthy subjects. Child-Pugh A subjects had similar estimated % geometric mean ratio for C max (106.7 %), and slightly greater estimated % geometric mean ratios for AUC0–t (133.0 %) and AUC0–∞ (122.8 %), versus healthy subjects. Mean elimination half-life was extended in subjects with hepatic impairment (43–47 vs 36 h). Ponatinib was generally well tolerated. A single serious AE (pancreatitis) in the Child-Pugh C group resolved with treatment.

Discussion

As no major differences in ponatinib single-dose PK were observed in patients with hepatic impairment versus healthy subjects, a reduction of ponatinib starting dose in these patients is not necessary, but caution is recommended when administering ponatinib to these patients.

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Acknowledgments

This study was sponsored by ARIAD Pharmaceuticals, Inc. Professional writing assistance for this publication was provided by Melinda Ramsey, Ph.D., and Francesca Balordi, Ph.D., from Medicus International New York, and was funded by ARIAD Pharmaceuticals, Inc.

Conflict of interest

N. N., D. D., J. D., and C. T. are employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc. D. S. is a paid consultant of ARIAD Pharmaceuticals, Inc. TM has no conflict of interest to declare.

Ethical standards

Written informed consent was obtained from all participants before their enrollment, and the protocol and informed consent form were approved by the institutional review board for the study center. This study was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice Guidelines and the requirements of the Declaration of Helsinki.

Author information

Authors and Affiliations

  1. DMPK and Preclinical Safety, ARIAD Pharmaceuticals, Inc., 26 Landsdowne St., Cambridge, MA, 02139, USA

    Narayana I. Narasimhan

  2. Orlando Clinical Research Center, 5055 S. Orange Ave, Orlando, FL, 32809, USA

    Thomas C. Marbury

  3. Sonnichsen Pharmaceutical Associates, LLC, 13 Hickory Place, Collegeville, PA, 19426, USA

    Daryl Sonnichsen

  4. Biostatistics, ARIAD Pharmaceuticals, Inc., 26 Landsdowne St., Cambridge, MA, 02139, USA

    David J. Dorer

  5. Clinical Operations, ARIAD Pharmaceuticals, Inc., 26 Landsdowne St., Cambridge, MA, 02139, USA

    Jeffrey Davis

  6. Clinical Research, ARIAD Pharmaceuticals, Inc., 26 Landsdowne St., Cambridge, MA, 02139, USA

    Christopher D. Turner

Authors
  1. Narayana I. Narasimhan
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  2. David J. Dorer
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  3. Jeffrey Davis
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  4. Christopher D. Turner
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  5. Thomas C. Marbury
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  6. Daryl Sonnichsen
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Corresponding author

Correspondence to Narayana I. Narasimhan.

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Narasimhan, N.I., Dorer, D.J., Davis, J. et al. Evaluation of pharmacokinetics and safety of ponatinib in subjects with chronic hepatic impairment and matched healthy subjects. Cancer Chemother Pharmacol 74, 341–348 (2014). https://doi.org/10.1007/s00280-014-2511-z

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  • DOI: https://doi.org/10.1007/s00280-014-2511-z

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