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Published on: September 8, 2017
A Bayesian population PK-PD model for ispinesib/docetaxel combination-induced myelosuppression
Steven J Kathman1, Daphne H Williams, Jeffrey P Hodge
1GlaxoSmithKline, Research Triangle Park, NC 27709, USA. skathmanjr@nc.rr.com
Cancer Chemotherapy and Pharmacology
|April 30, 2008
Summary
A Bayesian population PK/PD model characterized the relationship between ispinesib/docetaxel combination therapy and absolute neutrophil counts (ANC). This model helps optimize dosing for cancer treatment, minimizing neutropenia risks.
Area of Science:
- Pharmacology and Toxicology
- Oncology
- Mathematical Modeling
Background:
- Ispinesib inhibits mitotic spindle assembly, causing G2/M arrest.
- Docetaxel promotes microtubule assembly, leading to mitotic arrest.
- Both agents are CYP3A4 substrates/inhibitors, posing drug-interaction risks.
Purpose of the Study:
- To develop a Bayesian population pharmacokinetic/pharmacodynamic (PK/PD) model.
- To characterize the relationship between ispinesib/docetaxel combination and absolute neutrophil counts (ANC).
- To inform optimal dosing strategies and mitigate neutropenia.
Main Methods:
- Escalating doses of docetaxel and ispinesib administered on a 21-day schedule.
- Limited pharmacokinetic (PK) sampling and weekly ANC measurements.
- Nonlinear mixed-effects models and Bayesian methods utilized for PK/PD analysis, incorporating prior information.
Main Results:
- Twenty-four patients were treated; PK of both agents was well-characterized.
- No significant PK interaction observed between ispinesib and docetaxel.
- A robust PK/PD model for ANC was successfully fitted using Bayesian approaches.
Conclusions:
- The developed PK/PD model can simulate various dosing and scheduling scenarios for ispinesib/docetaxel.
- Bayesian methods effectively incorporated prior data, crucial for limited datasets.
- The model aids in optimizing cancer chemotherapy regimens to manage neutropenia.
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