Cancer Chemotherapy and Pharmacology

, Volume 74, Issue 2, pp 341–348

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

  • Narayana I. Narasimhan
  • David J. Dorer
  • Jeffrey Davis
  • Christopher D. Turner
  • Thomas C. Marbury
  • Daryl Sonnichsen
Original Article

DOI: 10.1007/s00280-014-2511-z

Cite this article as:
Narasimhan, N.I., Dorer, D.J., Davis, J. et al. Cancer Chemother Pharmacol (2014) 74: 341. doi:10.1007/s00280-014-2511-z

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 (Cmax) 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 Cmax, 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 Cmax (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.

Keywords

Ponatinib Tyrosine kinase inhibitor Hepatic impairment Pharmacokinetics Safety 

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Narayana I. Narasimhan
    • 1
  • David J. Dorer
    • 4
  • Jeffrey Davis
    • 5
  • Christopher D. Turner
    • 6
  • Thomas C. Marbury
    • 2
  • Daryl Sonnichsen
    • 3
  1. 1.DMPK and Preclinical SafetyARIAD Pharmaceuticals, Inc.CambridgeUSA
  2. 2.Orlando Clinical Research CenterOrlandoUSA
  3. 3.Sonnichsen Pharmaceutical Associates, LLCCollegevilleUSA
  4. 4.BiostatisticsARIAD Pharmaceuticals, Inc.CambridgeUSA
  5. 5.Clinical OperationsARIAD Pharmaceuticals, Inc.CambridgeUSA
  6. 6.Clinical ResearchARIAD Pharmaceuticals, Inc.CambridgeUSA

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