Portal de Periódicos da CAPES

Phase I and Pharmacologic Study of Oral (PEG-1000) 9-Aminocamptothecin in Adult Patients With Solid Tumors

1999; Lippincott Williams & Wilkins; Volume: 17; Issue: 7 Linguagem: Inglês

10.1200/jco.1999.17.7.2219

1527-7755

Maja J.A. de Jonge, Cornelis J. A. Punt, A. Hans Gelderblom, Walter J. Loos, V van Beurden, André Planting, Maria E.L. van der Burg, Lydia W.G.M. van Maanen, B.K. Dallaire, Jaap Verweij, D. J. Theo Wagener, Alex Sparreboom,

Neutropenia and Cancer Infections

9-Amino-20(S)-camptothecin (9-AC) is a specific inhibitor of topoisomerase-I. Recently, a bioavailability of approximately 48% for the oral PEG-1000 formulation was reported. We conducted a phase I and pharmacokinetic study of the oral PEG-1000 formulation of 9-AC to define the maximum-tolerated dose, toxicity profiles, pharmacokinetic-dynamic relationships, and preliminary antitumor activity in patients with solid tumors.Patients were treated with oral (PEG-1000) 9-AC given once a day for 7 or 14 days at doses ranging from 0.25 to 1.1 mg/m(2)/d; cycles were repeated every 21 days. For pharmacokinetic analysis, plasma sampling was performed on days 1 and 6 or 8 of the first course using a validated high-performance liquid chromatographic assay.Thirty patients were entered onto the study; three patients were not assessable for toxicity and response. Twenty-seven patients received a total of 89 courses. The dose-limiting toxicities (DLTs) were myelosuppression and diarrhea at a dose of 1.1 mg/m(2)/d for 14 days. Pharmacokinetics showed a substantial interpatient variation of the area under the plasma concentration-time curve (AUC) of 9-AC. The intrapatient variability was extremely small. A significant correlation was observed between the percentage decrease in WBC count and the AUC of 9-AC lactone (r(2) = 0.86). One partial response was noted in a patient with metastatic colorectal cancer.DLTs in this phase I study of oral 9-AC daily for 14 days every 21 days were myelosuppression and diarrhea. The recommended dose for phase II studies is 0.84 mg/m(2)/d. In view of the substantial interpatient variability in AUC and the availability of a limited sampling model, a pharmacokinetic guided phase II study should be considered.