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

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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 µg/l. The mean elimination half-life (T1/2 γ) was 20.7±9.0 h. The AUC0– 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.

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Bos, A., Vries, E., Dombernovsky, P. et al. Pharmacokinetics of MEN-10755, a novel anthracycline disaccharide analogue, in two phase I studies in adults with advanced solid tumours. Cancer Chemother Pharmacol 48, 361–369 (2001). https://doi.org/10.1007/s002800100350

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  • DOI: https://doi.org/10.1007/s002800100350

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