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Two-stage model-bas...
Two-stage model-based design of cancer phase I dose escalation trials : evaluation using the phase I program of barasertib (AZD1152)
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- Keizer, Ron J. (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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Zandvliet, Anthe S. (författare)
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Beijnen, Jos H. (författare)
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Schellens, Jan H. M. (författare)
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Huitema, Alwin D. R. (författare)
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(creator_code:org_t)
- 2011-05-28
- 2012
- Engelska.
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Ingår i: Investigational new drugs. - : Springer Science and Business Media LLC. - 0167-6997 .- 1573-0646. ; 30:4, s. 1519-1530
- Relaterad länk:
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https://link.springe...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Nyckelord
- Barasertib
- AZD1152
- Oncology
- Phase I
- Modeling and simulation
- Hematological toxicity
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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