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

ABSTRACT

PURPOSE: To evaluate the pharmacokinetics and safety of oral panobinostat in patients with advanced solid tumors and varying degrees of hepatic function. METHODS: Patients with advanced solid malignancies, acceptable bone marrow and renal function, and normal or impaired hepatic function, per NCI-ODWG criteria, were eligible. Initially patients received a single oral dose of 30 mg panobinostat for a 1-week pharmacokinetic study (core phase). Subsequently, patients received thrice-weekly panobinostat for as long as beneficial (extension phase safety assessment). Core phase serial blood samples for panobinostat and metabolite BJB432 assay were collected pre-dose and up to 96 h post-dose. RESULTS: Twenty-five patients were enrolled, median age 58 years (range 45-76). Fifteen patients had hepatic dysfunction (8 mild, 6 moderate, and 1 severe). Reductions in panobinostat plasma clearance were 30 and 51 %, with concomitant 43 and 105 % increase in exposure, for patients with mild and moderate hepatic dysfunction, respectively. Median peak plasma concentrations were 1.4-(mild) and 1.8-(moderate) fold higher than the normal group. Hepatic impairment did not alter panobinostat absorption with Tmax unchanged at 2 h. Geometric mean ratios of BJB432 to panobinostat plasma AUC0-∞ were similar in patients with normal, mild, or moderate hepatic impairment. Safety data were consistent with known safety profile of panobinostat in patients with advanced cancers and normal liver function. CONCLUSION: Despite increased plasma exposure, patients with mild or moderate hepatic dysfunction could be safely treated with the same starting dose of panobinostat as patients with normal hepatic function, with careful monitoring and dose adjustments as required.