Clinical trial simulation of docetaxel in patients with cancer as a tool for dosage optimization

Background Pharmacokinetic and pharmacodynamic analyses conducted during the development of docetaxel showed that patients with non–small‐cell lung cancer with high baseline α1‐acid glycoprotein levels had shorter time to progression and time to death. To assess whether such patients might benefit f...

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Bibliographic Details
Published in:Clinical pharmacology and therapeutics 2000-12, Vol.68 (6), p.677-687
Main Authors: Veyrat‐Follet, Christine, Bruno, René, Olivares, Robert, Rhodes, Gerald R., Chaikin, Philip
Format: Article
Language:English
Subjects:
Adult
Aged
Antineoplastic agents
Antineoplastic Agents, Phytogenic - pharmacokinetics
Antineoplastic Agents, Phytogenic - therapeutic use
Biological and medical sciences
Carcinoma, Non-Small-Cell Lung - blood
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - metabolism
Chemotherapy
Clinical Trials, Phase II as Topic
Clinical Trials, Phase III as Topic - methods
Computer Simulation
Dose-Response Relationship, Drug
Female
Humans
Lung Neoplasms - blood
Lung Neoplasms - drug therapy
Lung Neoplasms - metabolism
Male
Medical sciences
Middle Aged
Models, Biological
Multicenter Studies as Topic
Orosomucoid - metabolism
Paclitaxel - analogs & derivatives
Paclitaxel - pharmacokinetics
Paclitaxel - therapeutic use
Pharmacology. Drug treatments
Prognosis
Proportional Hazards Models
Regression Analysis
Reproducibility of Results
Survival Analysis
Taxoids
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Summary:Background Pharmacokinetic and pharmacodynamic analyses conducted during the development of docetaxel showed that patients with non–small‐cell lung cancer with high baseline α1‐acid glycoprotein levels had shorter time to progression and time to death. To assess whether such patients might benefit from dose intensification, we initiated a series of clinical trial simulations. Methods Pharmacokinetic and pharmacodynamic models for time to progression, death, and drop‐out were developed and validated with the use of phase II data from 151 patients with non–small‐cell lung cancer. The simulation process, in which these models were combined with a previously reported model for safety, was evaluated by comparison of the original phase II data with the predicted results. Simulations were undertaken for the evaluation of whether a trial (phase III) of 125 mg/m2 of docetaxel versus 100 mg/m2 of docetaxel in patients with high α1‐acid glycoprotein levels would show improved survival. Results The hazard models showed that lower α1‐acid glycoprotein levels, fewer number of organs involved, and higher docetaxel cumulative area under plasma concentration‐time curve were significantly associated with enhanced time to progression and time to death. The simulation process produced data patterns similar to actual patterns. In the simulated phase III trial, although median survival was slightly longer in the 125 mg/m2 docetaxel group than in the 100 mg/m2 group (5.49 months versus 5.31 months, respectively), the difference was significant in only 6 of 100 trials. Conclusions The low power to detect a difference due to dose intensification was the basis for the decision not to perform such a trial. The simulation exercise yielded valuable insight into how pharmacokinetic‐ and pharmacodynamic‐based simulation of clinical trials may have an impact on decision making in drug development. (Clin Pharmacol Ther 2000;68:677‐87.) Clinical Pharmacology & Therapeutics (2000) 68, 677–687; doi: 10.1067/mcp.2000.111948
ISSN:0009-9236
1532-6535
DOI:10.1067/mcp.2000.111948