|
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
| |
|
DOI
|
|
|
|
10.1007/S10637-017-0546-9
| |
|
Volume/pages
|
|
|
|
36
:3
(2018)
, p. 476-486
| |
|
ISI
|
|
|
|
000431954900014
| |
|
Pubmed ID
|
|
|
|
29177975
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|