A phase I and pharmacokinetic study of MAG-CPT, a water-soluble polymer conjugate of camptothecin

• Published in: British journal of cancer Vol. 87; no. 6; pp. 608 - 614
• Main Authors: SCHOEMAKER, N. E, VAN KESTEREN, C, GRAZIA PORRO, M, BEIJNEN, J. H, SCHELLENS, J. H. M, TEN BOKKEL HUININK, W. W, ROSING, H, JANSEN, S, SWART, M, LIEVERST, J, FRAIER, D, BREDA, M, PELLIZZONI, C, SPINELLI, R
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 09.09.2002
• Subjects: Acrylamides - administration & dosage; Acrylamides - adverse effects; Acrylamides - chemistry; Acrylamides - pharmacokinetics; Adult; Aged; Antineoplastic agents; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - adverse effects; Antineoplastic Agents, Phytogenic - pharmacokinetics; Biological and medical sciences; Camptothecin - administration & dosage; Camptothecin - adverse effects; Camptothecin - pharmacokinetics; Chemotherapy; Clinical; Female; Hematologic Diseases - chemically induced; Humans; Male; Maximum Tolerated Dose; Medical sciences; Middle Aged; Neoplasms - drug therapy; Pharmacology. Drug treatments; Urinary Bladder Diseases - chemically induced; Antineoplastic agent; Human; Enzyme; Maximal dose; Controlled release form; DNA topoisomerase; Enzyme inhibitor; Polymer; Malignant tumor; Biological activity; Water soluble compound; Alkaloid; Chemotherapy; Isomerases; Limit dose; Treatment; Phase I trial; Dosage form; Conjugation; Pharmacokinetics
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6600516

Polymeric drug conjugates are a new and experimental class of drug delivery systems with pharmacokinetic promises. The antineoplastic drug camptothecin was linked to a water-soluble polymeric backbone (MAG-CPT) and administrated as a 30 min infusion over 3 consecutive days every 4 weeks to patients with malignant solid tumours. The objectives of our study were to determine the maximal tolerated dose, the dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document anti-tumour activity. The starting dose was 17 mg m(-2) day(-1). Sixteen patients received 39 courses at seven dose levels. Maximal tolerated dose was at 68 mg m(-2) day(-1) and dose-limiting toxicities consisted of cumulative bladder toxicity. MAG-CPT and free camptothecin were accumulated during days 1-3 and considerable amounts of MAG-CPT could still be retrieved in plasma and urine after 4-5 weeks. The half-lives of bound and free camptothecin were equal indicating that the kinetics of free camptothecin were release rate dependent. In summary, the pharmacokinetics of camptothecin were dramatically changed, showing controlled prolonged exposure of camptothecin. Haematological toxicity was relatively mild, but serious bladder toxicity was encountered which is typical for camptothecin and was found dose limiting.