Yazarlar : Narasimhan NI1, Dorer DJ, Davis J, Turner CD, Marbury TC, Sonnichsen D.

Yayın : Cancer Chemother Pharmacol. 2014 Jun 17

Yayın Yılı : 2014

Pubmed Linki : http://www.ncbi.nlm.nih.gov/pubmed/24934866

Konu : Lösemi

Literatür İçeriği : Evaluation of pharmacokinetics and safety of ponatinib in subjects with chronic hepatic impairment and matched healthy subjects. Narasimhan NI1, Dorer DJ, Davis J, Turner CD, Marbury TC, Sonnichsen D. Author information 1DMPK and Preclinical Safety, ARIAD Pharmaceuticals, Inc., 26 Landsdowne St., Cambridge, MA, 02139, USA, narayana.narasimhan@ariad.com. 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. PMID: 24934866 [PubMed - as supplied by publisher]

Literatür Arşivi