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

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 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.

Phase II studies of polymer-doxorubicin (PK1, FCE28068) in the treatment of breast, lung and colorectal cancer

“…In contrast to the hints of activity seen here, a related strategy using a polymer carrier to deliver the topoisomerase I inhibitor camptothecin (PNU166148) recently reported negative results in a phase I and pharmacokinetic study involving 23 patients with various types of cancer (6 colorectal, 4 unknown primary, 2 each head and neck, NSCLC, renals and one of each adrenal, cervical, oesophageal, Ewing's, gastric, mesothelioma and prostate) (23). The linkage of camptothecin to the polymer carrier was designed for pHcatalysed esterolytic cleavage, in contrast to the proteasebased release of doxorubicin employed here, making it hard to compare the pharmacology of the two drug conjugates.…”

“…The polymer carrier also permits incorporation of membrane active peptides or targeting agents into the conjugate structure, the latter designed to enhance receptor-mediated uptake into tumour cells or organs containing tumour metastases, and increase the exposure of the tumour to active drug while minimizing exposure of normal tissues (31). Thoughtful design of macromolecular drug conjugates should yield a range of new approaches to cancer treatment with potentially significant benefits, and several have already progressed as far as clinical evaluation in phase I studies (23,(31)(32)(33).…”

Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle

“…When CPT was conjugated to linear PEG, the PK profiles of the released CPT in animals (32) and humans (33,34) showed the same form of the dynamics as observed for CRLX101. Likewise, the MAG-CPT gave released CPT dynamics of the same type (35,36). However, the polymeric micelle of SN-38 shows the same behavior for released SN-38 in animals (37) and humans (28), as does PEG-bound SN-38 in animals (38) and humans (39).…”

Polymer-drug conjugates: Recent development in clinical oncology

“…Results presented in an earlier clinical study showed serious bladder toxicity which became dose limiting. Patients with higher plasma AUC values had the more severe symptoms of renal toxicity [54].…”