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30.06.2017 | Review Article | Ausgabe 1/2018

Clinical Pharmacokinetics 1/2018

Clinical Pharmacokinetics and Pharmacodynamics of Panobinostat

Zeitschrift:
Clinical Pharmacokinetics > Ausgabe 1/2018
Autoren:
Mathilde Van Veggel, Elsbeth Westerman, Paul Hamberg

Abstract

Histone deacetylase (HDAC) inhibitors cause an increase in acetylation that leads to an increase in DNA transcription and accumulation of different proteins, reducing cell proliferation and inducing cell death. Panobinostat is a first-in-line HDAC inhibitor approved for treating multiple myeloma in combination with bortezomib and dexamethasone. It is a pan-deacetylase inhibitor and therefore inhibits not only HDAC but also other deacetylases. The main mechanism of action of panobinostat is to inhibit HDAC, which causes cell cycle arrest and apoptosis, leading to it being an antineoplastic drug. Pooled data of multiple-dose studies show that an oral dose of panobinostat 20 mg resulted in a maximum plasma concentration (C max) of 21.6 ng/mL approximately 1 h after administration, while doses between 10 and 30 mg resulted in dose proportional plasma levels. The absolute bioavailability of panobinostat is 21.4%, and it is moderately bound to plasma proteins. Renal impairment does not influence the intrinsic pharmacokinetics of panobinostat, however hepatic impairment causes an increase in the plasma concentrations of this drug. Therefore, starting treatment at lower doses could be considered in patients with mild to moderate hepatic impairment. Different ethnic backgrounds have an influence on the pharmacokinetics of panobinostat; however, due to major interindividual variability, no dose adjustment is recommended. The area under the concentration–time curve of panobinostat changes significantly under cytochrome P450 (CYP) 3A4 inhibitors, CYP3A4 and CYP2D6 inducers, and P-glycoprotein inhibitors. Panobinostat itself is a CYP2D6 inhibitor, which influences the plasma levels of the CYP2D6 substrate dexamethasone. The main side effects of panobinostat are diarrhea, peripheral neuropathy, asthenia and fatigue; hematologic side effects include neutropenia, thrombocytopenia, and lymphocytopenia.

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