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 72 day
71. Sixteen patients received 39 courses at seven dose levels. Maximal tolerated dose was at 68 mg m 72 day 71 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.
The purpose of this phase II trial was to compare the efficacy, safety and pharmacokinetics of four irinotecan schedules for the treatment of metastatic colorectal cancer. In total, 174 5-fluorouracil pretreated patients were randomised to: arm A (n ¼ irinotecan as a 14-day continuous infusion q3 weeks. No significant differences in efficacy across the four arms were observed, although a shorter time to treatment failure was noted for arm D (1.7 months; P ¼ 0.02). Overall response rates were in the range 5 -11%. Secondary end points included median survival (6.4 -9.4 months), and time to progression (2.7 -3.8 months) and treatment failure (1.7 -3.2 months). Similarly, there were no significant differences in the incidence of grade 3 -4 toxicities, although the toxicity profile between arms A, B, and C and D did differ. Generally, significantly less haematologic toxicity, alopecia and cholinergic syndrome were observed in arm D; however, there was a trend for increased gastrointestinal toxicity. Irinotecan is an effective and safe second-line treatment for colorectal cancer. The schedules examined yielded equivalent results, indicating that there is no advantage of the prolonged vs short infusion schedules.41
A rapid, sensitive, and specific high-performance liquid chromatography (HPLC) method for the simultaneous determination of irinotecan (CPT-11) and its active metabolite SN-38 in human plasma is described. The analytes are quantified as the totals of their carboxylate and lactone form. The sample pretreatment consisted of a simple protein precipitation with acetonitrile-methanol (1:1, v/v), after which CPT-11 and SN-38 were quantitatively converted to their carboxylate form by adding 0.01 mol/L sodium tetraborate (pH, 9). Chromatography was carried out on a Zorbax SB-C18 column with fluorescence detection. The method has been validated, and stability tests under various clinically relevant conditions have been performed. The lower limit of quantification (LLOQ) was 5.0 ng/mL for CPT-11 and 0.5 ng/mL for SN-38. Standard concentration ranges were linear between 5 and 1,500 ng/mL for CPT-11 and between 0.5 and 100 ng/mL for SN-38. This assay is simple, rapid, and very useful for therapeutic monitoring of CPT-11 and SN-38.
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