A phase I, open-label, multicenter study to evaluate the pharmacokinetics and safety of oral panobinostat in patients with advanced solid tumors and varying degrees of renal function

作者：Sharma Sunil; Witteveen Petronella O; Lolkema Martijn P; Hess Dagmar; Gelderblom Hans^*; Hussain Syed A; Porro Maria G; Waldron Edward; Valera Sue zette; Mu Song

来源：Cancer Chemotherapy and Pharmacology, 2015, 75(1): 87-95.

DOI：10.1007/s00280-014-2612-8

• Renal impairment
• Panobinostat
• Pan-deacetylase inhibitor
• Histone
• Phase I

This study assessed the pharmacokinetics and safety of oral panobinostat and its metabolite BJB432 in patients with advanced solid tumors and normal to severely impaired renal function.
Patients with varying degrees of renal impairment, defined by their 24-h baseline urine creatinine clearance (as normal, mild, moderate or severe), received a single oral dose of 30 mg panobinostat. Serial plasma samples were collected pre-dose and up to 96-h post-dose. Serial urine samples were collected for 24-h post-dose. Following the serial PK sampling, patients received 30 mg oral panobinostat thrice weekly for as long as the patient had benefit. Pharmacokinetic parameters were derived using non-compartmental analysis.
Thirty-seven patients were enrolled, and median age was 64 (range 40-81) years. Eleven patients had normal renal function; 10, 10, and 6 patients had mild, moderate, and severe renal impairment, respectively. Geometric means of AUC(0-a) in the normal, mild, moderate, and severe groups were 224.5, 144.3, 223.1, and 131.7 ng h/mL, respectively. Geometric mean ratio of BJB432 to parent drug plasma AUC(0-a) was 0.64 in the normal group and increased to 0.81, 1.13, and 1.20 in the mild, moderate, and severe groups, respectively. The fraction excreted as unchanged panobinostat was small (< 2 %), with a large variability. The renal clearance of panobinostat and tolerability was similar across all four groups.
Systemic exposure to panobinostat did not increase with severity of renal impairment, and the drug was tolerated equally; thus, patients with renal impairment do not require starting dose adjustments.

• 出版日期2015-1