Pharmacokinetics of MEN-10755, a novel anthracycline disaccharide analogue, in two phase I studies in adults with advanced solid tumours

Citation
Ame. Bos et al., Pharmacokinetics of MEN-10755, a novel anthracycline disaccharide analogue, in two phase I studies in adults with advanced solid tumours, CANC CHEMOT, 48(5), 2001, pp. 361-369
Citations number
28
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER CHEMOTHERAPY AND PHARMACOLOGY
ISSN journal
0344-5704 → ACNP
Volume
48
Issue
5
Year of publication
2001
Pages
361 - 369
Database
ISI
SICI code
0344-5704(200111)48:5<361:POMANA>2.0.ZU;2-F
Abstract
The doxorubicin analogue MEN-10755 has been identified as a compound with p romising antitumour activity based on structure-activity studies of a new s eries of anthracycline disaccharides. The high antitumour activity of MEN-1 0755 in human tumour xenografts, including doxorubicin-resistant xenografts , and its unique pharmacological and biological properties made this novel disaccharide analogue an interesting candidate for clinical evaluation. Two pharmacokinetic phase I studies with different dosing schedules were perfo rmed in adults with solid refractory malignancies. The pharmacokinetics of MEN-10755 were studied after a 15-min i.v. infusion given once every 3 week s or once every week for 3 weeks followed by I week rest. Plasma and urine levels of MEN-10755 were measured by HPLC with fluorescent detection. It wa s possible to combine the pharmacokinetic results of the two studies becaus e there was no accumulation of MEN-10755 before the next infusion of MEN-10 755 in the weekly study with I week rest. The administered dose levels on d ay I in this study were all in the lower range from the 3-weekly study. The postinfusion plasma kinetics of MEN-10755 were best described by a triexpo nential model. The plasma peak levels (C-max) of MEN-10755 showed a linear relationship with the administered dose. Peak plasma MEN-10755 levels range d between 474 and 21,587 mug/l. The mean elimination half-life (T-1/2 gamma ) was 20.7 +/- 9.0 h. The AUC(0-infinity) was proportional to the administe red dose. The mean plasma clearance of MEN-10755 was 6.0 +/- 2.2 1/h per m( 2) with a mean volume of distribution (V-ss) of 95.6 +/- 43.4 1/m(2). The m ean renal excretion of unchanged drug within 24 h was 4.3 +/- 1.8 %. Compar ed to epirubicin and doxorubicin, the pharmacokinetics of MEN-10755 were ch aracterized by an approximately twofold shorter terminal half-life, a much lower total plasma clearance and a much smaller volume of distribution.