Evaluation of pharmacokinetics and safety of ponatinib in subjects with chronic hepatic impairment and matched healthy subjects
- Narayana I. NarasimhanAffiliated withDMPK and Preclinical Safety, ARIAD Pharmaceuticals, Inc. Email author
- , David J. DorerAffiliated withBiostatistics, ARIAD Pharmaceuticals, Inc.
- , Jeffrey DavisAffiliated withClinical Operations, ARIAD Pharmaceuticals, Inc.
- , Christopher D. TurnerAffiliated withClinical Research, ARIAD Pharmaceuticals, Inc.
- , Thomas C. MarburyAffiliated withOrlando Clinical Research Center
- , Daryl SonnichsenAffiliated withSonnichsen Pharmaceutical Associates, LLC
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This study evaluated the effects of chronic hepatic impairment on the single-dose pharmacokinetics (PK) of the tyrosine kinase inhibitor ponatinib.
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.
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.
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.
KeywordsPonatinib Tyrosine kinase inhibitor Hepatic impairment Pharmacokinetics Safety
- Evaluation of pharmacokinetics and safety of ponatinib in subjects with chronic hepatic impairment and matched healthy subjects
Cancer Chemotherapy and Pharmacology
Volume 74, Issue 2 , pp 341-348
- Cover Date
- Print ISSN
- Online ISSN
- Springer Berlin Heidelberg
- Additional Links
- Tyrosine kinase inhibitor
- Hepatic impairment
- Industry Sectors
- Author Affiliations
- 1. DMPK and Preclinical Safety, ARIAD Pharmaceuticals, Inc., 26 Landsdowne St., Cambridge, MA, 02139, USA
- 4. Biostatistics, ARIAD Pharmaceuticals, Inc., 26 Landsdowne St., Cambridge, MA, 02139, USA
- 5. Clinical Operations, ARIAD Pharmaceuticals, Inc., 26 Landsdowne St., Cambridge, MA, 02139, USA
- 6. Clinical Research, ARIAD Pharmaceuticals, Inc., 26 Landsdowne St., Cambridge, MA, 02139, USA
- 2. Orlando Clinical Research Center, 5055 S. Orange Ave, Orlando, FL, 32809, USA
- 3. Sonnichsen Pharmaceutical Associates, LLC, 13 Hickory Place, Collegeville, PA, 19426, USA