title: Pharmacokinetics of MEN-10755, a novel anthracycline disaccharide analogue, in two phase I studies in adults with advanced solid tumours.
abstract: 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.
authors.forename: A M
authors.initials: AM
authors.lastname: Bos
authors.forename: E G
authors.initials: EG
authors.lastname: de Vries
authors.forename: P
authors.initials: P
authors.lastname: Dombernovsky
authors.forename: S
authors.initials: S
authors.lastname: Aamdal
authors.forename: D R
authors.initials: DR
authors.lastname: Uges
authors.forename: D
authors.initials: D
authors.lastname: Schrijvers
authors.forename: J
authors.initials: J
authors.lastname: Wanders
authors.forename: M W
authors.initials: MW
authors.lastname: Roelvink
authors.forename: A R
authors.initials: AR
authors.lastname: Hanauske
authors.forename: S
authors.initials: S
authors.lastname: Bortini
authors.forename: A
authors.initials: A
authors.lastname: Capriati
authors.forename: A E
authors.initials: AE
authors.lastname: Crea
authors.forename: J B
authors.initials: JB
authors.lastname: Vermorken
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D002648:Child; D004187:Disaccharides / Q000493:pharmacokinetics*; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004187:Disaccharides; D004317:Doxorubicin; C107602:sabarubicin