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

Abstract

5007 Panobinostat, 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 dysfunction PK parameters, median range Normal hepatic function (n 10) Mild hepatic dysfunction (n 5TUF1-1) Moderate hepatic dysfunction (n 3) Tmax (hr) 2 0.5-7 2 0.5-2 2 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\frac{1}{4}\) \end{document} Cmax (ng/mL) 19.0 6.9-61.8 27.0 17.4-56.3 31.2 15.1-37.3 AUC0-inf (nghr/mL) 184 42.7-347 285 75.8-342 276 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\frac{161}{425}\) \end{document} t1/2 (hr) 28.9 14.2-36.6 25.0 17.5-39.3 23.6 16.3-40.6 One patient was excluded from the PK analysis because of emesis. AUC0-inf, area under the concentration-time curve from zero to infinity; Cmax, maximum concentration; t1/2, half-life; Tmax, time to maximum plasma concentration. 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.