Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat LBH589, an orally active histone deacetylase inhibitorReportar como inadecuado




Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat LBH589, an orally active histone deacetylase inhibitor - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Cancer Chemotherapy and Pharmacology

, Volume 68, Issue 3, pp 805–813

First Online: 26 June 2011Received: 04 April 2011Accepted: 09 June 2011

Abstract

PurposePanobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat.

MethodsPatients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5–9, ketoconazole was administered. On day 8, a single panobinostat dose was co-administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward.

ResultsIn the presence of ketoconazole, there was 1.6- and 1.8-fold increase in Cmax and AUC of panobinostat, respectively. No substantial change in Tmax or half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1-*3 and CYP3A5*3-*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia 64%, and urine analysis suggested renal phosphate wasting.

ConclusionsCo-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary.

KeywordsPanobinostat LBH589 Histone deacetylase inhibitor CYP3A Previously presented in part at the Annual Meeting of the American Society of Clinical Oncology 2008 oral presentation.

ClinicalTrials.gov identifier: NCT 00503451.

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Autor: Paul Hamberg - Margaret M. Woo - Lin-Chi Chen - Jaap Verweij - Maria Grazia Porro - Lily Zhao - Wenkui Li - Diane van de

Fuente: https://link.springer.com/







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