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

Abstract

Purpose 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. Methods 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. Results 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 AUC0–∞ 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 AUC0–∞ 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. Conclusion 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.