Population pharmacokinetics of intravenous and oral panobinostat in patients with hematologic and solid tumors.

Purpose: The study aimed to characterize the population pharmacokinetics of panobinostat, a pan-deacetylase inhibitor that has demonstrated efficacy in combination with bortezomib and dexamethasone in patients with multiple myeloma.

Methods: A nonlinear mixed-effect model was used to fit plasma panobinostat concentration-time data collected from patients across 14 phase 1 and phase 2 trials following either oral or intravenous (IV) administration. The model was used to estimate bioavailabilities of the two oral formulations and the effects of demographic and clinical covariates on the central volume of distribution and clearance of panobinostat.

A clinical investigation of inhibitory effect of panobinostat on CYP2D6 substrate in patients with advanced cancer.

Purpose: Panobinostat is a potent oral pan-deacetylase inhibitor with promising clinical activity in hematologic malignancies. Panobinostat was shown to inhibit CYP2D6 activity in vitro; thus understanding the magnitude of the potential clinical inhibition of panobinostat on co-medications that are CYP2D6 substrates becomes important.

Methods: This study evaluated the effects of co-administration of panobinostat with a sensitive CYP2D6 substrate, dextromethorphan (DM), in patients with advanced cancer who have functional CYP2D6 genes.

A randomized dose-escalation study to assess the safety, tolerability, and pharmacokinetics of ruxolitinib (INC424) in healthy Japanese volunteers.

Ruxolitinib (INC424), a potent and selective oral Janus kinase 1 and 2 inhibitor, was recently approved by the US food and drug administration for the treatment of intermediate or high-risk myelofibrosis. The safety, tolerability, and pharmacokinetics (PK) of ruxolitinib have been extensively evaluated in healthy subjects and patients. The present study is the first to investigate the PK and tolerability of ruxolitinib in the Japanese population.

A phase I dose-escalation study of intravenous panobinostat in patients with lymphoma and solid tumors.

Purpose: Panobinostat, a pan-deacetylase inhibitor, is a promising anti-cancer agent that increases acetylation of proteins associated with growth and survival pathways of malignant cells. The primary objective of this phase I dose-escalation study was to determine the maximum tolerated dose (MTD) of intravenous (i.v.

Characterizing the disposition, metabolism, and excretion of an orally active pan-deacetylase inhibitor, panobinostat, via trace radiolabeled 14C material in advanced cancer patients.

Purpose: Elucidating the metabolic profile of anticancer agent panobinostat is essential during drug development. Disposition, metabolism, and excretion profiles were characterized using trace radiolabeled (14)C-panobinostat in four patients with advanced cancer.

Methods: Oral (14)C-panobinostat was administered and serial blood, plasma, and excreta samples were collected up to 7 days postdose for radioactivity and pharmacokinetic analyses.

The effect of food on the bioavailability of panobinostat, an orally active pan-histone deacetylase inhibitor, in patients with advanced cancer.

Purpose: Panobinostat is a novel oral pan-deacetylase inhibitor with promising anti-cancer activity. The study aimed to determine the influence of food on the oral bioavailability of panobinostat.

Methods: This multicenter study consisted of a randomized, three-way crossover, food-effect study period (cycle 1) followed by single-agent panobinostat continual treatment phase in patients with advanced cancer.

Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (LBH589), an orally active histone deacetylase inhibitor.

Purpose: Panobinostat 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.

Methods: Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period.

A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer.

Purpose: Histone deacetylase inhibitors have demonstrated anticancer activity against a range of tumors. We aimed to define the maximum tolerated dose, toxicity, activity, and pharmacokinetics of oral panobinostat, a pan-deacetylase inhibitor, alone and in combination with docetaxel for the treatment of castration-resistant prostate cancer (CRPC).

Methods: Sixteen patients were enrolled, eight in each arm.

Inhibition of drug metabolizing cytochrome P450s by the aromatase inhibitor drug letrozole and its major oxidative metabolite 4,4'-methanol-bisbenzonitrile in vitro.

Purpose: To determine the inhibitory potency of letrozole and its main human metabolite, 4,4'-methanol-bisbenzonitrile, on the activities of eight cytochrome P450 (CYP) enzymes.

Methods: Letrozole and its metabolite were incubated with human liver microsomes (HLMs) (or expressed CYP isoforms) and NADPH in the absence (control) and presence of the test inhibitor.

Results: Letrozole was a potent competitive inhibitor of CYP2A6 (K (i) 4.