Related Experiment Video
Updated: Mar 31, 2026

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Panobinostat PK/PD profile in combination with bortezomib and dexamethasone in patients with relapsed and
Song Mu1, Yoshiaki Kuroda2, Hirohiko Shibayama3
1Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. song.mu@novartis.com.
Purpose:
Panobinostat, a potent pan-deacetylase inhibitor, improved progression-free survival (PFS) in patients with relapsed and refractory multiple myeloma when combined with bortezomib and dexamethasone in a phase 3 trial, PANORAMA-1. This study aims to explore exposure-response relationship for panobinostat in this combination in a phase 1 trial, B2207 and contrast with data from historical single-agent studies.
Methods:
Panobinostat plasma concentration-time profiles were obtained in patients from PANORAMA-1 (n = 12) and B2207 (n = 12) trials. Overall response rates (ORR) and major adverse events (AE) by panobinostat exposure were investigated in the B2207 trial. Panobinostat PK data from combination trials were contrasted with data from single-agent studies.
Results:
At maximum tolerated dose (MTD), the geometric mean of panobinostat area under curve from 0 to 24 h (AUC0-24) was 47.5 ng h/mL (77 % CV), and maximum plasma concentration (Cmax) was 8.1 ng/mL (90 % CV). These values were comparable with exposure data obtained in PANORAMA-1, but were 20 % lower than those without dexamethasone, and ∼ 50 % lower from single-agent trials, likely due to enzyme induction by dexamethasone. Higher levels of panobinostat exposure were associated with higher response rates and higher incidences of diarrhea and thrombocytopenia.
Conclusions:
Apparent panobinostat exposure-AE and exposure-ORR relationships were observed when combined with bortezomib and dexamethasone in the treatment of patients with relapsed and refractory multiple myeloma. The addition of dexamethasone facilitated best response even though plasma exposure of panobinostat was reduced. Combination with a strong enzyme inducer should be avoided in future trials to prevent further reduction of panobinostat exposure.
Related Concept Videos
Dosage Regimens: Partial Pharmacokinetic Parameters
Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu
Pharmacokinetics in Obese Patients: Drug Metabolism and Excretion
Pharmacokinetics in Obese Patients: Drug Absorption and Distribution
Drug Accumulation During Multiple Dosing: Intermittent IV Infusions
Pharmacokinetic–Pharmacodynamic Relationship: Dose to Pharmacological Effect

