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

• Published in: Cancer chemotherapy and pharmacology Vol. 48; no. 5; pp. 361 - 369
• Main Authors: BOS, A. M. E, DE VRIES, E. G. E, CAPRIATI, A, CREA, A. E. G, VERMORKEN, J. B, DOMBERNOVSKY, P, AAMDAL, S, UGES, D. R. A, SCHRIJVERS, D, WANDERS, J, ROELVINK, M. W. J, HANAUSKE, A. R, BORTINI, S
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.11.2001
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents - pharmacokinetics; Biological and medical sciences; Chemotherapy; Child; Disaccharides - pharmacokinetics; Doxorubicin - analogs & derivatives; Doxorubicin - pharmacokinetics; Female; Humans; Kidney - metabolism; Male; Medical sciences; Middle Aged; Neoplasms - drug therapy; Neoplasms - metabolism; Pharmacology. Drug treatments; Antineoplastic agent; Human; Solid tumor; Intravenous administration; Maximal dose; Administration schedule; Clearance; Malignant tumor; Doxorubicin; Disaccharide; Blood plasma; Increasing dose; Chemotherapy; Treatment; Distribution volume; Analog; Phase I trial; Adult; Advanced stage; Anthracyclins; Pharmacokinetics; Half life
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s002800100350

The doxorubicin analogue MEN-10755 has been identified as a compound with promising antitumour activity based on structure-activity studies of a new series of anthracycline disaccharides. The high antitumour activity of MEN-10755 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 performed in adults with solid refractory malignancies. The pharmacokinetics of MEN-10755 were studied after a 15-min i.v. infusion given once every 3 weeks or once every week for 3 weeks followed by 1 week rest. Plasma and urine levels of MEN-10755 were measured by HPLC with fluorescent detection. It was possible to combine the pharmacokinetic results of the two studies because there was no accumulation of MEN-10755 before the next infusion of MEN-10755 in the weekly study with 1 week rest. The administered dose levels on day 1 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 triexponential model. The plasma peak levels (Cmax) of MEN-10755 showed a linear relationship with the administered dose. Peak plasma MEN-10755 levels ranged between 474 and 21,587 microg/l. The mean elimination half-life (T(1/2gamma)) was 20.7+/-9.0 h. The AUC(0-infinity) was proportional to the administered dose. The mean plasma clearance of MEN-10755 was 6.0+/-2.2 l/h per m2 with a mean volume of distribution (Vss) of 95.6+/-43.4 l/m2. The mean renal excretion of unchanged drug within 24 h was 4.3+/-1.8%. Compared to epirubicin and doxorubicin, the pharmacokinetics of MEN-10755 were characterized by an approximately twofold shorter terminal half-life, a much lower total plasma clearance and a much smaller volume of distribution.