Publication
Title
Hepatic safety analysis of trabectedin: results of a pharmacokinetic study with trabectedin in patients with hepatic impairment and experience from a phase 3 clinical trial
Author
Abstract
Purpose Trabectedin is metabolized by the liver and has been associated with transient, noncumulative transaminase elevation. Two recent studies further characterize hepatic tolerability with trabectedin therapy: a phase 1 pharmacokinetic study (Study #1004; NCT01273493) in patients with advanced malignancies and hepatic impairment (HI), and a phase 3 study (Study #3007; NCT01343277) of trabectedin vs. dacarbazine in patients with advanced sarcomas and normal hepatic function. Methods In Study #1004, patients received a single 3-h intravenous (IV) infusion of trabectedin: control group, trabectedin 1.3 mg/m(2); HI group (baseline total bilirubin >1.5 and <= 3x upper limit of normal [ULN]; AST and ALT <= 2.5 x ULN). trabectedin 0.58 or 0.9 mg/ m(2). In Study #3007, the trabectedin group received 1.5 mg/m(2) by 24-h IV infusion every 3 weeks until disease progression or unacceptable toxicity. Results In Study #1004, dose-normalized trabectedin exposure was higher in HI patients (n = 6) versus controls (n = 9) (geometric mean ratios [90% CI] AUC(l)(ast): 1.97 [1.20; 3.22]). In Study #3007, following trabectedin administration, 90% of patients had elevated ALT (32% grade 3-4) and 84% had elevated AST (17% grade 3-4). Transaminase elevations were transient and noncumulative. Progression-free survival was similar in patients with grade 3-4 hepatotoxicity (n = 109) versus grade 0-2 hepatotoxicity (n = 231) (median [95% CI]: 4.63 [4.01, 5.85] months versus 3.55 [2.73, 4.63] months; P = 0.545, HR = 0.91 [0.68-1.23]). Conclusion Trabectedin treatment of patients with HI results in higher plasma exposures. Hepatotoxicity in patients with normal liver function can be effectively addressed through dose reductions and delays.
Language
English
Source (journal)
Investigational new drugs. - Boston, Mass.
Publication
Boston, Mass. : 2018
ISSN
0167-6997
Volume/pages
36 :3 (2018) , p. 476-486
ISI
000431954900014
Pubmed ID
29177975
Full text (Publisher's DOI)
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 12.06.2018
Last edited 20.09.2021
To cite this reference