Pharmacokinetics Of Panobinostat Research Articles

Pharmacokinetics of panobinostat: Inter-species difference in metabolic stability.

Panobinostat is a potent pan-HDAC inhibitor that has been tested in multiple studies for the treatment of brain tumors. There have been contrasting views surrounding its efficacy for the treatment of tumors in the CNS following systemic administration when examined in different models or species. We conducted experiments using three different mouse strains or genotypes to have a more comprehensive understanding of the systemic as well as the CNS distributional kinetics of panobinostat. Our study found that panobinostat experienced rapid degradation in vitro in FVB mouse matrices and a faster degradation rate was observed at 37{degree sign}C compared with room temperature and 4{degree sign}C, suggesting that the in vitro instability of panobinostat was due to enzymatic metabolism. Panobinostat also showed inter-strain and inter-species differences in the in vitro plasma stability; and was stable in human plasma. The objective of this study was to examine the in vitro metabolic stability of panobinostat in different matrices and assess the influence of that metabolic stability on the in vivo pharmacokinetics and CNS delivery of panobinostat. Importantly, the plasma stability in various mouse strains was not reflected in the in vivo systemic pharmacokinetic behavior of panobinostat. Several hypotheses arise from this finding, including: the binding of panobinostat to red blood cells, the existence of competing endogenous compounds to enzyme(s), the distribution into tissues with a lower level of enzymatic activity or the metabolism occurring in the plasma is a small fraction of the total metabolism in vivo Significance Statement Panobinostat showed different in vitro degradation in plasma from different mouse strains and genotypes. However, despite the differences surrounding in vitro plasma stability, panobinostat showed similar in vivo pharmacokinetic behavior in different mouse models. This suggests that the inter-strain difference in enzymatic activity did not affect the in vivo pharmacokinetic behavior of panobinostat and its CNS distribution in mice. This lack of translation between in vitro metabolism assays and in vivo disposition can confound drug development.

A Phase 1b Study of Panobinostat in Combination with Idarubicin and Ara-C in Patients with High-Risk Acute Myeloid Leukemia

A Phase 1b Study of Panobinostat in Combination with Idarubicin and Ara-C in Patients with High-Risk Acute Myeloid Leukemia

Effects of Hepatic Function on the Pharmacokinetics and Safety of Panobinostat in Patients with Advanced Cancer: A Phase I Study

Abstract 5007Panobinostat, an orally active hydroxamic acid derivative, is a potent class I/II/IV pan-deacetylase inhibitor that has shown promising clinical activity in hematologic and nonhematologic malignancies. Patients with cancer frequently have impaired renal or hepatic function. The major clearance pathway of panobinostat is metabolism mediated by cytochrome P450 3A4 (CYP3A4) and non-CYP pathways. Panobinostat and its metabolites are excreted in similar amounts in liver (54.3) and kidneys (40.6); however, the effects of impaired renal and hepatic function on panobinostat pharmacokinetics (PK) have not yet been elucidated.This study was designed to assess whether hepatic dysfunction has an impact on the PK of panobinostat and its safety when compared with that of patients with normal hepatic function. Patients with advanced cancer, Eastern Cooperative Oncology Group performance status (PS) 0 to 2, normal bone marrow function, and serum creatinine 1.5 upper limit of normal were enrolled. Hepatic function was categorized as normal (control), mild, moderate, or severe according to the baseline aspartate aminotransferase and total bilirubin levels per National Cancer InstituteCancer Treatment Evaluation Program criteria. Serial plasma samples were collected up to 96 hours following a single PK test dose of panobinostat 30 mg and its concentrations assessed by liquid chromatography tandem mass spectrometry. PK parameters were derived from individual plasma concentrationtime data using non-compartmental analysis.One week after the PK test dose, patients started continuous panobinostat 30 mg 3 times per week every week. Dose was modified according to tolerability. Ten patients with normal, 6 mildly, and 3 moderately impaired hepatic function were enrolled. The median age was 58 years (10 male; 9 female), and 95 of the patients had PS 0 to 1. Thirteen patients (7 normal (70), 4 mild (67), and 2 moderate (67)) experienced grade 3 toxicity suspected to be drug related. Grade 3 or 4 thrombocytopenia occurred in 3 patients in the normal group (30). Grade 3 nonhematologic adverse events included fatigue (4 normal (40), 1 mild (17), 1 moderate (33)), diarrhea (2 normal (20), 1 mild (17)), nausea (3 normal (30), 1 mild (17)), and vomiting (1 normal (10), 1 mild (17)). One patient in the moderate group was discontinued from the study because of grade 3 vasculitis (purpuric rash, proteinuria, anemia, and renal dysfunction). In these heavily pretreated patients, disease stabilization was noted in 3 patients, one with endometrial cancer, one with adenocarcinoma of the lung, and one with prostate cancer. The PK results from 19 patients of this ongoing study are summarized in the table below. The currently available results suggest that the PK and safety of panobinostat are comparable between patients with normal hepatic function and those with mild or moderate liver dysfunctionPK parameters, median rangeNormal hepatic function (n 10)Mild hepatic dysfunction (n 5TUF1-1)Moderate hepatic dysfunction (n 3)Tmax (hr)2 0.5-72 0.5-22 14Cmax (ng/mL)19.0 6.9-61.827.0 17.4-56.331.2 15.1-37.3AUC0-inf (nghr/mL)184 42.7-347285 75.8-342276 161425t1/2 (hr)28.9 14.2-36.625.0 17.5-39.323.6 16.3-40.6AUC0-inf, area under the concentration-time curve from zero to infinity; Cmax, maximum concentration; t1/2, half-life; Tmax, time to maximum plasma concentration.TUF1-1One patient was excluded from the PK analysis because of emesis. Disclosures:Hess:Novartis: Equity Ownership. Porro:Novaratis Pharma AG: Employment. Hengelage:Novartis Pharma AG: Employment, Equity Ownership. St-Pierre:Novartis Pharma AG: Employment. Gazi:Novartis Pharma AG: Employment. Li:Novartis Pharmaceuticals: Employment, Equity Ownership. Woo:Novartis Pharmaceutical Corporation: Employment, Equity Ownership. Sharma:Novartis: Research Funding.

Effects of Renal Function on the Pharmacokinetics of Panobinostat in Patients with Advanced Cancer: A Phase I Study

Abstract 5001Panobinostat is a potent class I/II/IV oral pan-deacetylase inhibitor which has shown promising clinical activity in patients with multiple myeloma and myelofibrosis, some with compromised renal and hepatic functions. The metabolism mediated by cytochrome P450 3A4 (CYP3A4) and non-CYP pathways is the major clearance pathway of panobinostat, with drug and metabolites being excreted in nearly similar amounts by liver/bile (54.3) and kidneys (40.6). However, the effects of impaired renal and hepatic function on panobinostat pharmacokinetics (PK) have not been elucidated.This study was designed to assess the impact of renal dysfunction on the PK and safety of panobinostat when compared to that of patients with normal renal function. Patients with advanced cancer, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 2, AST/ALT 2.5 ULN, normal bone marrow, and varying degrees of renal function were enrolled. Renal function was categorized as normal (as control), mild, moderate, or severe according to baseline 24-hour urine creatinine clearance (CrCL). Serial blood and urine panobinostat samples collected up to 96 and 24 hours, respectively, following a single PK test dose of 30 mg panobinostat were assessed for plasma and urine concentrations by liquid chromatography tandem mass spectrometry. PK parameters were derived from individual plasma or urine concentrationtime data using non-compartmental analysis. The following week, patients continued to receive panobinostat 30 mg orally 3 times a week. Dose was modified according to tolerability.PK results from 19 patients (15 male, 4 female) in this ongoing study are tabulated below. Median age was 66 years, and 13/19 patients had ECOG PS 1. Safety results were available in 18 patients. The most frequent drug-related adverse events (AEs) were grade (Gr) 34 thrombocytopenia in 7 patients (2 normal, 2 mild, 3 moderate) and Gr 3 fatigue in 5 patients (1 normal, 1 mild, 3 moderate). Other drug-related Gr 3 AEs included nausea, diarrhea, and hyperphosphatemia (1 normal patient each); asthenia and anemia (1 mild patient each); and ventricular bigeminy and dehydration (1 moderate patient). Two deaths on therapy not suspected to be study drugrelated occurred in the normal group. Although efficacy is not the primary study objective, PR was noted in 1 moderate patient with bladder cancer while SD was noted in 5 patients (2 pancreatic, 1 ovarian, 1 bladder and 1 renal cancer) as best overall response in these heavily pre-treated patients.The currently available results unexpectedly showed that patients with renal dysfunction did not have higher panobinostat exposures than the control group and the PK of panobinostat did not seem to have a distinct rank-order relationship with the severity of renal dysfunctionPK parameters median rangeRenal Function ClassificationNormal n7(CrCL 80 mL/min)Mild n6(50 CrCL 80 mL/min)Moderate n6(30 CrCL 50 mL/min)Tmax (hr)1.0 0.5-41.0 0.5-41.0 0.5-2Cmax (ng/mL)36.7 30.0-107.014.4 5.8-33.522.8 9.5-52.3AUC0-inf (nghr/mL)371 180441108 76234202 78329t1/2(hr)32.9 25.2-42.836.0 23.7-55.634.3 31.4-35.4ClR/F (L/hr)1.6 0.4-2.71.4 0.5-2.82.1 0.2-3.8Xu0-24hr ( of dose)1.8 1.2-4.00.6 0.2-1.30.7 0.2-1.9AUC0-inf, area under the concentration-time curve from zero to infinity; Cmax, maximum concentration; t1/2, half-life; Tmax, time to maximum plasma concentration; Xu0-24h, percentage of drug excreted in urine; ClR/F, apparent renal clearance. Disclosures:Sharma:Novartis: Research Funding. Valera:Novartis Pharmaceuticals: Employment. Li:Novartis Pharmaceuticals: Employment, Equity Ownership. Mires:Novartis Pharmaceuticals: Employment. Porro:Novaratis Pharma AG: Employment. Woo:Novartis Pharmaceutical Corporation: Employment, Equity Ownership. Hess:Novartis: Equity Ownership.

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

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. 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 20mg 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). 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 1-1.5h 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. Food produced minor changes in oral panobinostat exposure; thus, panobinostat can be given without regard to food intake in future clinical studies.

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

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). 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. 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. 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.

Influence of food on the pharmacokinetics (PK) of panobinostat (LBH589), an orally active histone deacetylase inhibitor, in patients with advanced cancer

2550 Background: The effect of food on the bioavailability and PK of panobinostat (PAN) are of considerable importance in allowing appropriate dosing of chronic oral cancer therapy. Methods: Patients (pts) with advanced cancer received 20 mg PAN twice a week of a 21-day cycle and were randomized to receive 1 of 6 treatment sequences where PAN PK was evaluated weekly under fasting, high fat and normal breakfast. Serial blood samples were collected for PAN PK evaluations on Days 1, 8, and 15. Plasma PAN concentrations were measured by LC-MS-MS. PK parameters were estimated by using non-compartmental analysis. Results: A total of 34 patients were evaluated. PAN was generally well tolerated with no significant lab, ECG, or other safety concerns. No residual PAN concentrations were detected in pre-dose samples on Days 8 and 15. Meal conditions and PAN PK parameters expressed as either mean (CV%) or median [range] or ratio are described in the Table . The overall exposure and inter-patient variability (CV 59%) remained unchanged with or without food, whereas Cmax was transiently reduced (<45%) by food. Although tumor response was not the main objective, a pt with recurrent RCC, following sunitinib and sorafenib treatment, has achieved a PR after ∼6 cycles of PAN and is continued on study. Conclusions: Since the overall extent of absorption and variability was not changed due to food, PAN administration with or without food is unlikely to significantly impact systemic PAN exposure in cancer patients. PAN can be administered without regards to food in future studies. [Table: see text] [Table: see text]

A drug interaction study between ketoconazole and panobinostat (LBH589), an orally active histone deacetylase inhibitor, in patients with advanced cancer

2501 Background: The effects of ketoconazole (keto), a potent CYP3A inhibitor, on the pharmacokinetics (PK) of panobinostat (PAN) were investigated in an open-label, multicenter, cross-over, single sequence study. Methods: Patients (pts) with advanced solid tumors or NHL received single-agent PAN at 20 mg on Day 1 and single-agent keto at 400 mg daily on Days 5–9. On Day 8, PAN 20 mg was administered 1 hour after keto. All pts had adequate organ function and ECOG performance status <2. Serial plasma samples were collected for PAN PK evaluations on Days 1 and 8 and pre- and post-dose keto samples on Days 5, 8, and 9. Plasma PAN and keto concentrations were measured by LC-MS-MS. PK parameters were estimated by using non-compartmental analysis. Genotyping analysis of CYP3A4*1B, CYP3A5*2, *3, *6 and *7 were performed by using AmpliChip CYP450. Results: Fourteen Caucasian patients (9M, 5F) were enrolled with a median age of 59. Fourteen pts had homozygous wide-type CYP3A4*1A genotype, 11 pts had homozygous CYP3A5*3, and three pts had heterozygous CYP3A5*1/*3 genotype. No residual PAN concentrations were detected in pre-dose samples on Day 8. PAN PK parameters were calculated as either mean (CV%), median [range] or ratio (see Table). Single-dose PAN did not affect keto concentrations. Co-administration of keto and PAN increased PAN Cmax and AUC by 1.6- and 1.7-fold, respectively, but with no change in Tmax. There was no apparent difference in PAN PK between pts who carried CYP3A5*1 allele and homozygous CYP3A5*3 carriers. Conclusions: The less than 2-fold increase in PAN AUC upon co-administration suggests that CYP3A contribution to the total clearance of PAN is low. The observed interaction is not considered clinically relevant, as PAN doses are at least 2-fold greater than 20 mg (40 and 60 mg) have been safely administered in pts. CYP3A4 inhibitors should have no major impact on the exposure of PAN and may be co-administered when medically necessary. [Table: see text] [Table: see text]