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Physiologically-based pharmacokinetic model predictions of panobinostat (LBH589) as a victim and perpetrator of drug-drug interactions

Einolf, Heidi and Lin, Wen and Wang, Lai and Gu, Helen and Chun, Dung Y. and Mangold, James B. and He, Handan (2017) Physiologically-based pharmacokinetic model predictions of panobinostat (LBH589) as a victim and perpetrator of drug-drug interactions. Drug Metabolism and Disposition.

Abstract

Panobinostat (Farydak®) is an orally active hydroxamic acid derived histone deacetylase inhibitor for the treatment of relapsed/refractory multiple myeloma. Based upon recombinant cytochrome P450 (CYP) kinetic analyses in vitro, panobinostat oxidative metabolism in human liver microsomes was found to be primarily mediated by CYP3A4 with lower contributions by CYP2D6 and CYP2C19. Panobinostat was also shown to be an in vitro reversible and time-dependent inhibitor of CYP3A4, and a reversible inhibitor of CYP2D6 and CYP2C19. Based upon a previous clinical drug-drug interaction study with ketoconazole (KTZ), the contribution of CYP3A4 in vivo was estimated to be ~40%. Using clinical pharmacokinetic (PK) data from several trials including the KTZ DDI study, a physiologically-based pharmacokinetic (PBPK) model was built to predict panobinostat PK after single and multiple doses (within 2-fold of observed values for most trials) and the clinical DDI with KTZ (predicted and observed AUC ratios of 1.8). The model was then applied to predict the drug interaction with the strong CYP3A4 inducer, rifampin (RIF) and sensitive CYP3A4 substrate, midazolam (MDZ) in lieu of clinical trials. Panobinostat exposure was predicted to decrease in the presence of RIF (65%) and inconsequentially increase MDZ exposure (4%). Additionally, PBPK modeling was used to examine the effects of stomach pH on the absorption of panobinostat in humans. The absorption of panobinostat is not expected to be affected by increases in stomach pH. The results from these studies impacted the product label, providing guidance for Farydak® dosing recommendations when combined with other drugs.

Item Type: Article
Date Deposited: 07 Nov 2017 00:45
Last Modified: 07 Nov 2017 00:45
URI: https://oak.novartis.com/id/eprint/32871

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