Effects of Renal Function on the Pharmacokinetics of Panobinostat in Patients with Advanced Cancer: A Phase I Study
Autor: | Neeraj Agarwal, Jason Li, Nicole Hagner, Margaret M. Woo, Martijn P. Lolkema, Sunil Sharma, Emile E. Voest, Petronella O. Witteveen, Maria Grazia Porro, Dagmar Hess, Derek Mires, Sue-zette Valera |
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Rok vydání: | 2011 |
Předmět: |
Kidney
medicine.medical_specialty Performance status business.industry Immunology Cmax Renal function Cell Biology Hematology Pharmacology medicine.disease Biochemistry Gastroenterology Hyperphosphatemia chemistry.chemical_compound medicine.anatomical_structure Pharmacokinetics Tolerability chemistry Internal medicine Panobinostat Medicine business |
Zdroj: | Blood. 118:5001-5001 |
ISSN: | 1528-0020 0006-4971 |
Popis: | Abstract 5001 Panobinostat 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 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\frac{180}{441}\) \end{document}108 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\frac{76}{234}\) \end{document}202 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\frac{78}{329}\) \end{document}t1/2(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 0.2-1.9 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; 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. |
Databáze: | OpenAIRE |
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