Population Pharmacokinetics of Panobinostat (LBH589) in Patients with Advanced Solid Tumors and Hematologic Malignancies Following Intravenous and Oral Administration.

Panobinostat (LBH589), a hydroxamic acid derivative, is one of the most potent deacetylase inhibitors (DACi), with anti-tumor activity in a wide variety of preclinical xenograft models, and has shown promising clinical activity in patients with Hodgkin lymphoma and multiple myeloma. A population pharmacokinetic (PopPK) analysis was performed to characterize the extent and variability of panobinostat exposure in patients with advanced cancer and to evaluate the influence of selected covariates on exposure.

Panobinostat concentrations in plasma were evaluated in 500 patients enrolled in five Phase I studies and four Phase II studies as asingle-agent administration. Patients received oral panobinostat at doses of 10–80 mg on Days 1, 3, and 5, weekly [QW], or every other week [QOW], or on Days 1 and 4 QW in three Phase I oral studies. Intravenous (i.v.) panobinostat was delivered at doses from 1.2 to 20 mg/m² in 4 schedules (Days 1–7; or Days 1–3 QW or QOW; or once weekly for 3 weeks) in two Phase I i.v. studies. Panobinostat was also orally administered at 20 mg, on Days 1, 3 and 5 QW, in patients with cutaneous T-cell lymphoma, chronic myelogenous leukemia, and multiple myeloma in four Phase II oral studies. Panobinostat PopPK was characterized by a compartmental non-linear mixed-effects model.

Panobinostat concentration–time data were well described by a linear 3-compartment model with first-order absorption. The model estimated the population median (CV%) of the total clearance (CL) to be 28.6 L/h (78%) and the volume of distribution (V) 27.2 L (54.8%). Absolute oral bioavailability is 30%. The relative bioavailabilities of oral formulations 1 (Phase II formulation) and 2 (Phase I formulation) are 17% and 23%, respectively. The analysis showed no effect on panobinostat clearance by gender, race, co-medications, disease state, or renal function as measured by plasma creatinine clearance. Body surface area (BSA 1.4–3.4 m²) and age (16–88 years) in the ranges studied were non-linear covariates for panobinostat clearance and volume.

The pharmacokinetics of panobinostat are linear and time independent. BSA may have clinical utility in predicting panobinostat clearance. The PopPK model generated from this study allows for future pharmacokinetic–pharmacodynamic correlation and application in optimizing the use of panobinostat.

Savelieva Praz:Novartis: Employment. Woo:Novartis: Employment. Weber:Novartis Pharma AG: Employment. Hirawat:Novartis: Employment. Paul:Novartis: Employment. Schindler:Novartis: Employment. Fisch:Novartis : Employment.