Pharmacokinetics and pharmacodynamics of 9-aminocamptothecin infused over 72 hours in phase II studies.

Abstract

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) microg/m2/h, and 9-AC was infused at 35.4 microg/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.

• Authors: H Minami, T E Lad, M K Nicholas, E E Vokes, M J Ratain
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 5 Issue 6 Pg. 1325-30 (Jun 1999) ISSN: 1078-0432 [Print] United States
• PMID: 10389915 (Publication Type: Clinical Trial, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anticonvulsants
• Granulocyte Colony-Stimulating Factor
• 9-aminocamptothecin
• Camptothecin

Topics

• Adult
• Aged
• Anticonvulsants (administration & dosage)
• Blood Cell Count (drug effects)
• Brain Neoplasms (drug therapy)
• Camptothecin (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)
• Carcinoma, Non-Small-Cell Lung (drug therapy)
• Carcinoma, Squamous Cell (drug therapy)
• Drug Administration Schedule
• Female
• Glioma (drug therapy)
• Granulocyte Colony-Stimulating Factor (administration & dosage)
• Head and Neck Neoplasms (drug therapy)
• Humans
• Infusions, Intravenous
• Logistic Models
• Lung Neoplasms (drug therapy)
• Male
• Metabolic Clearance Rate
• Middle Aged