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Pharmacokinetics and Pharmacodynamics of 9-Aminocamptothecin Infused Over 72 Hours in Phase II Studies¹

Sections of Hematology/Oncology [H. M., E. E. V., M. J. R.] and Neurology [M. K. N.], Department of Medicine, Cancer Research Center [E. E. V., M. J. R.], Department of Radiation and Cellular Oncology [E. E. V.], Phase II Cooperative Network [T. E. L., M. K. N., E. E. V., M. J. R.], and Committee on Clinical Pharmacology [M. J. R.], The University of Chicago, Chicago, Illinois 60637, and Section of Hematology/Oncology, University of Illinois at Chicago, Chicago, Illinois 60612 [T. E. L.]

A novel derivative of camptothecin, 9-aminocamptothecin (9-AC), is currently under Phase II evaluation in various cancers. Exceptionally mild toxicities were observed in patients with brain tumors who were treated with anticonvulsants. To investigate a pharmacokinetic interaction between 9-AC and anticonvulsants, and to evaluate the pharmacodynamics of 9-AC, we investigated the clinical pharmacology of 9-AC, administered by a 72-h infusion, in three Phase II studies. Plasma concentrations of total 9-AC (lactone plus carboxylate) at a steady state were measured in 56, 10, and 14 patients with non-small cell lung cancer, malignant glioma, and head and neck cancer, respectively. For lung cancer or glioma patients, 9-AC was infused at 45 (51 patients) or 59 (15 patients) µg/m²/h, and 9-AC was infused at 35.4 µg/m²/h in head and neck cancer patients. All glioma patients had been treated with phenytoin or carbamazepine. 9-AC clearance did not differ among the dosage rates, but differed according to the diseases (P = 0.002). Glioma patients had a higher clearance (1.0–18.0; median, 2.0 liters/h/m²) than lung cancer patients (0.3–5.1; median, 0.9 liters/h/m²). A logistic regression model described the relationship between the 9-AC concentration and the probability of grade 4 neutropenia, which was the main toxicity. Observed incidences of grade 4 neutropenia for patients with model-predicted probability of 0–20%, 20–40%, and 40–100% were 10%, 32%, and 67%, respectively, and corresponded to 9-AC concentration of <54, 54–86, and >86 ng/ml, respectively. Anticonvulsants seem to induce the clearance of 9-AC, and the concentration of 9-AC predicts the probability of grade 4 neutropenia.

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