Phase I clinical and pharmacokinetic trial of the podophyllotoxin derivative NK611 administered as intravenous short infusion
| Autor: | Axel-R. Hanauske, Wolfgang E. Berdel, Ch. Manegold, K. Burk, A. Kaeser-Fröhlich, Andreas Hüttmann, Rassmann I, H.H. Fiebig, R. Thödtmann, M. Mross |
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| Rok vydání: | 1999 |
| Předmět: |
Adult
Male medicine.medical_specialty Nausea medicine.medical_treatment Antineoplastic Agents Pharmacology Gastroenterology Cohort Studies Pharmacokinetics In vivo Internal medicine Neoplasms Granulocyte Colony-Stimulating Factor medicine Humans Pharmacology (medical) Infusions Intravenous Etoposide Aged Podophyllotoxin Chemotherapy business.industry Middle Aged medicine.disease Oncology Hepatocellular carcinoma Area Under Curve Toxicity Female medicine.symptom business medicine.drug |
| Zdroj: | Investigational new drugs. 16(4) |
| ISSN: | 0167-6997 |
| Popis: | Background: NK611 is a novel podophyllotoxin derivative. Compared with etoposide, NK611 carries a dimethyl-amino group at the D-glucose moiety. The antitumor activity of NK611 showed to be equal or superior to etoposide in a variety of in vitro and in vivo tumor models. The aim of our present study was to determine the maximum tolerated dose and the dose-limiting toxicities of NK611 administered as intravenous infusion over 30 min every 28 days. Patients and methods: 45 patients (7 female, 38 male; median age 54 [range 37–73]) were enrolled. In a first stage, NK611 was administered without hematopoietic growth factor support; in a second stage, G-CSF was used for further dose escalation. Toxicities were assessed using WHO-criteria. Results: Initially, the dose was escalated from 60 mg/m2 to 120 mg/m2. In a second patient cohort, doses were further escalated with G-CSF support with doses ranging from 140 mg/m2 to 250 mg/m2. Dose-limiting toxicities were granulocytopenia and thrombocytopenia. Non-hematologic toxicities consisted of alopecia, mild nausea, and infection. Four partial responses were observed: two at 200 mg/m2 (pleural mesothelioma, response duration 7 months, and non-small cell lung cancer, response duration 13 months), and two at 250 mg/m2 (hepatocellular carcinoma, response duration 7 months, and non-small cell lung cancer, response duration 2 months). Pharmacokinetic analyses were performed in all patients. Using an open 3-compartment model, the terminal half-life (t1/2γ) was 14.7 ± 3.7 h. The AUC at 250 mg/m2 was determined to be 330 ± 147 μg/mlh, the plasma clearance of NK611 was 16.2 ± 8.2 ml/min · m2 and the Vss was 16.8 ± 3.3 l/m2. Protein binding of NK611 was 98.7%. Conclusion: the recommended dose for clinical Phase II studies is 120 mg/m2 without G-CSF support and 200 mg/m2 with G-CSF support. |
| Databáze: | OpenAIRE |
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