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Clinical Trial
. 2002 Sep 9;87(6):608-14.
doi: 10.1038/sj.bjc.6600516.

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

N E Schoemaker  1 , C van Kesteren, H Rosing, S Jansen, M Swart, J Lieverst, D Fraier, M Breda, C Pellizzoni, R Spinelli, M Grazia Porro, J H Beijnen, J H M Schellens, W W ten Bokkel Huinink
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Free PMC article
Clinical Trial

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

N E Schoemaker et al. Br J Cancer. .
Free PMC article

Abstract

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.

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Figures

Figure 1
Figure 1
Chemical structure of MAG-CPT.
Figure 2
Figure 2
Mean plasma concentration-time curves of bound campto thecin and free camptothecin of patients treated with 68 mg m−2 day−1 MAG-CPT.
Figure 3
Figure 3
Plot of AUC∞ of bound camptothecin (left panel) and free camptothecin (right panel) as a function of the accumulative administered dose of MAG-CPT during course 1. Bars indicate mean values.
Figure 4
Figure 4
Plot of the AUC0–96 of bound camptothecin against the occurrence of dysuria during all courses of individual patients, P of difference is 0.014. Bars indicate mean values.
Figure 5
Figure 5
The percentage decreases in WBC (solid line) and ANC (dashed line) during the first course vs the daily dose. The lines indicate the best fit of the data to the sigmoidal maximal effect pharmacodynamic model (coefficient of correlation is 0.75 and 0.84 for WBC and ANC, respectively).
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