Panobinostat PK/PD profile in combination with bortezomib and dexamethasone in patients with relapsed and relapsed/refractory multiple myeloma

• Published in: European journal of clinical pharmacology Vol. 72; no. 2; pp. 153 - 161
• Main Authors: Mu, Song, Kuroda, Yoshiaki, Shibayama, Hirohiko, Hino, Masayuki, Tajima, Takeshi, Corrado, Claudia, Lin, Rong, Waldron, Edward, Binlich, Florence, Suzuki, Kenshi
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2016; Springer Nature B.V
• Subjects: Adult; Aged; Antineoplastic Agents - adverse effects; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - blood; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomedical and Life Sciences; Biomedicine; Bortezomib - adverse effects; Bortezomib - blood; Bortezomib - pharmacokinetics; Bortezomib - therapeutic use; Clinical Trial; Dexamethasone - adverse effects; Dexamethasone - pharmacology; Dexamethasone - therapeutic use; Double-Blind Method; Drug Resistance, Neoplasm; Drug therapy; Humans; Hydroxamic Acids - adverse effects; Hydroxamic Acids - blood; Hydroxamic Acids - pharmacokinetics; Hydroxamic Acids - therapeutic use; Indoles - adverse effects; Indoles - blood; Indoles - pharmacokinetics; Indoles - therapeutic use; Maximum Tolerated Dose; Middle Aged; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Neoplasm Recurrence, Local; Pharmacology; Pharmacology/Toxicology; Panobinostat; Clinical trials; Histone deacetylase inhibitor; Pharmacodynamics; Pharmacokinetics
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-015-1967-z

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.