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. RESULTS: A total of 7834 samples from 581 patients were analyzed. Panobinostat pharmacokinetic parameters were best characterized by a three-compartment model with first-order absorption and elimination. Bioavailability was 21.4 %. Median clearance was 33.1 L/h. Interindividual variability in clearance was 74 %. For Caucasian patients of median age 61 years, area under the curve (AUC) decreased from 104 to 88 ng · h/mL as body surface area (BSA) increased from the first to third quartiles, 1.8 to 2.1 m(2). For Caucasian patients of median BSA 1.9 m(2), AUC decreased from 102 to 95 ng · h/mL as age increased from the first to third quartiles, 51 to 70 years. For patients of median BSA and median age, AUC ranged across the four race categories from 80 to 116 ng · h/mL. Covariate analysis showed no impact on panobinostat clearance and volume by patients' sex, tumor type, kidney function, liver markers, or coadministered medications. However, separate analyses of dedicated studies have demonstrated effects of liver impairment and CYP3A4 inhibition. CONCLUSIONS: Although covariate analyses revealed significant effects of body size, age, and race on panobinostat pharmacokinetics, these effects were minor compared to the interindividual variability and therefore not clinically relevant when dosing panobinostat in populations similar to those studied.

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.) panobinostat administered on different dosing schedules in patients with advanced solid tumors or lymphoma. Secondary objective was to characterize safety and tolerability, pharmacokinetic profiles, and activities of the i.v. formulation. METHODS: i.v. panobinostat was administered at escalating doses on a daily (days 1-3 and 8-10 of a 21-day cycle; days 1-3 and 15-17 of a 28-day cycle) or weekly (days 1, 8, and 15 of a 28-day cycle; days 1 and 8 of a 21-day cycle) schedule, and safety and tolerability were monitored. Serial blood samples were collected following dosing for pharmacokinetic and pharmacodynamic analyses. RESULTS: The MTD for the daily administration schedule was 7.2 g/m(2), whereas the MTD for the weekly schedule was 20.0 mg/m(2). In addition to fatigue and cardiac arrhythmias, including prolonged QTcF, DLTs associated with the study drug were principally due to myelosuppressive effects. Maximum concentrations and bioavailability of i.v. panobinostat increased dose-proportionally across all doses evaluated. CONCLUSIONS: Based on the results of this study and others, the i.v. formulation of panobinostat was well tolerated in many patients, but concerns remain regarding its potential suitability outside the study setting due to potential electrocardiogram abnormalities. Therefore, further development will focus on the panobinostat oral formulation.

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. Forty subjects were randomized to receive single (10-100 mg) and multiple (10 and 25 mg every 12 h) doses of ruxolitinib or placebo. Cohorts were sequentially enrolled based on the outcome of safety assessments. Ruxolitinib was rapidly absorbed, and its exposure increased dose proportionally up to 100 mg. The half-life of ruxolitinib was approximately 3 h, and drug accumulation was not observed after repeated dosing at a 12-h dosing interval. Decreasing absolute neutrophil counts were observed in five Japanese subjects treated once (100 mg, n = 1) or twice (10 mg, n = 3; 25 mg, n = 1) daily. These events were manageable and reversible upon drug discontinuation. Orally administered ruxolitinib was well tolerated in healthy Japanese volunteers. There were no apparent differences in the safety or PK of ruxolitinib between Japanese and non-Japanese subjects.

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. Patients received 60 mg DM alone on day 1, panobinostat at 20 mg alone on days 3 and 5, and both agents on day 8. Plasma concentrations of DM and its metabolite dextrorphan (DX) were determined by liquid chromatography-tandem mass spectrometry following serial blood collections on day 1 (DM alone) and day 8 (in combination with panobinostat). RESULTS: Panobinostat increased DM exposure by 64 % [geometric mean ratio (GMR), 1.64 (90 % confidence interval (CI), 1.17-2.31)] and DX exposure by 29 % (GMR, 1.29 [90 % CI, 1.10-1.51]). These results indicated that panobinostat weakly inhibited a sensitive CYP2D6 substrate in cancer patients by increasing DM exposure by less than twofold. CONCLUSION: Safety monitoring of sensitive CYP2D6 substrates with narrow therapeutic index is recommended when co-administering with panobinostat in future clinical practice.

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. Metabolites in plasma and excreta were profiled using liquid chromatography (LC) with radiometric detection, and their structures elucidated using LC-tandem mass spectrometry. RESULTS: Radioactivity (≥87 %) was recovered in excreta within 7 days: 44-77 % dose recovery in feces and 29-51 % in urine. Circulating radioactivity was localized in plasma, with minor partitioning to blood. Minimal recovery in feces (<3.5 % of dose) suggested near-complete oral absorption. Maximum concentrations (median, 21.2 ng/mL; range, 13.4-41.5 ng/mL) were achieved within 1 h, and median (range) terminal half-life, apparent oral, and renal clearance was 30.7 h (27.6-33.2 h), 209 L/h (114-248 L/h), and 3.20 L/h (2.4-5.5 L/h), respectively. Approximately 40 metabolites were circulating in plasma, with biotransformation occurring primarily at the hydroxamic acid side chain and ethyl-methyl indole moiety. Metabolites derived from modification of the hydroxamic acid side chain were inactive for deacetylase inhibition. CONCLUSIONS: Panobinostat and its metabolites were excreted in similar amounts through the kidneys and liver with good dose recovery. Panobinostat was rapidly absorbed and cleared primarily through metabolism. Over half of its clearance was attributed to non-CYP-mediated pathways. Thus, CYP-mediated drug-drug interactions with panobinostat are predicted to be minor.

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. Patients received panobinostat 20 mg twice weekly, and panobinostat pharmacokinetics was investigated on days 1, 8, and 15 with a randomly assigned sequence of three prandial states (fasting, high-fat, and normal breakfast). RESULTS: Thirty-six patients were assessed for the food effect on pharmacokinetics and safety in cycle 1, after which 29 patients continued treatment, receiving single-agent panobinostat. Safety and antitumor activity were assessed during the extension period. Panobinostat systemic exposure was marginally reduced (14-16%) following food [geometric mean ratio (GMR) of the AUC(0-∞)/high-fat breakfast/fasting, 0.84 (90% confidence interval {CI}, 0.74-0.96); normal breakfast/fasting, 0.86 (90% CI, 0.75-1.00)], and interpatient variability (coefficient of variation, 59%) remained essentially unchanged with or without food. Panobinostat C (max) was reduced by 44% (high-fat) and 36% (normal) with median T (max) prolonged by 1-1.5 h following food. Panobinostat was well tolerated, with thrombocytopenia, fatigue, nausea, and vomiting as common adverse events, and demonstrated antitumor activity with one patient with a partial response and six patients with stable disease as best response. CONCLUSIONS: Food produced minor changes in oral panobinostat exposure; thus, panobinostat can be given without regard to food intake in future clinical studies.

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. 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. RESULTS: In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in C (max) and AUC of panobinostat, respectively. No substantial change in T (max) 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. CONCLUSIONS: Co-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.

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. Eligible patients had CRPC and adequate organ function. In arm I, oral panobinostat (20 mg) was administered on days 1, 3, and 5 for 2 consecutive weeks followed by a 1-week break. In arm II, oral panobinostat (15 mg) was administered on the same schedule in combination with docetaxel 75 mg/m(2) every 21 days. RESULTS: Dose-limiting toxicities were grade 3 dyspnea (arm I) and grade 3 neutropenia >7 days (arm II). In arm I, all patients developed progressive disease despite accumulation of acetylated histones in peripheral blood mononuclear cells. In arm II, five of eight patients (63%) had a >or=50% decline in prostate-specific antigen (PSA), including one patient whose disease had previously progressed on docetaxel. CONCLUSIONS: Oral panobinostat with and without docetaxel is feasible, and docetaxel had no apparent effect on the pharmacokinetics of panobinostat. Since preclinical studies suggest a dose-dependent effect of panobinostat on PSA expression, and other phase I data demonstrate that intravenous panobinostat produces higher peak concentrations (>20- to 30-fold) and area under the curve (3.5x-5x), a decision was made to focus the development of panobinostat on the intravenous formulation to treat CRPC.

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) 4.6 +/- 0.05 microM and 5.0 +/- 2.4 microM in HLMs and CYP2A6, respectively) and a weak inhibitor of CYP2C19 (K (i) 42.2 microM in HLMs and 33.3 microM in CYP2C19), while its metabolite showed moderate inhibition of CYP2C19 and CYP2B6. Letrozole or its metabolite had negligible effect on other CYPs. CONCLUSIONS: Based on the in vitro K (i) values, letrozole is predicted to be a weak inhibitor of CYP2A6 in vivo. Letrozole and its major human metabolite show inhibitory activity towards other CYPs, but clinically relevant drug interactions seem less likely as the K (i) values are above the therapeutic plasma concentrations of letrozole.