Abstract | INTRODUCTION: Modeling and simulation of pharmacokinetics and pharmacodynamics has previously been shown to be potentially useful in designing Phase I programs of novel anti- cancer agents that show hematological toxicity. In this analysis, a two-stage model-based trial design was evaluated retrospectively using data from the Phase I program with the aurora kinase inhibitor barasertib. METHODS: Data from two Phase I trials and four regimens were used (n = 79). Using barasertib-hydroxy QPA plasma concentrations and neutrophil count data from only study 1A, a PKPD model was developed and subsequently used to predict the MTD and a safe starting dose for the other trials. RESULTS: The PKPD model based on data from the first study adequately described the time course of neutrophil count fluctuation. The two-stage model-based design provided safe starting doses for subsequent phase I trials for barasertib. Predicted safe starting dose levels were higher than those used in two subsequent trials, but lower than used in the other trial. DISCUSSION: The two-stage approach could have been applied safely to define starting doses for alternative dosing strategies with barasertib. The limited improvement in efficiency for the phase I program of barasertib may have been due to the fact that starting doses for the studied phase I trials were already nearly optimal. CONCLUSION: Application of the two-stage model-based trial design in Phase I programs with novel anti- cancer drugs that cause haematological toxicity is feasible, safe, and may lead to a reduction in the number of patient treated at sub-therapeutic dose-levels.
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Authors | Ron J Keizer, Anthe S Zandvliet, Jos H Beijnen, Jan H M Schellens, Alwin D R Huitema |
Journal | Investigational new drugs
(Invest New Drugs)
Vol. 30
Issue 4
Pg. 1519-30
(Aug 2012)
ISSN: 1573-0646 [Electronic] United States |
PMID | 21626115
(Publication Type: Evaluation Study, Journal Article)
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Chemical References |
- 2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate
- Antineoplastic Agents
- Organophosphates
- Quinazolines
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Topics |
- Antineoplastic Agents
(administration & dosage, pharmacokinetics, therapeutic use)
- Clinical Trials, Phase I as Topic
(methods)
- Dose-Response Relationship, Drug
- Humans
- Leukocyte Count
- Maximum Tolerated Dose
- Models, Biological
- Organophosphates
(administration & dosage, pharmacokinetics, therapeutic use)
- Quinazolines
(administration & dosage, pharmacokinetics, therapeutic use)
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