Simulation-based systematic review of imatinib population pharmacokinetics and PK-PD relationships in chronic myeloid leukemia (CML) patients

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Serval ID
serval:BIB_12575934C0A0
Type
Inproceedings: an article in a conference proceedings.
Publication sub-type
Abstract (Abstract): shot summary in a article that contain essentials elements presented during a scientific conference, lecture or from a poster.
Collection
Publications
Institution
Title
Simulation-based systematic review of imatinib population pharmacokinetics and PK-PD relationships in chronic myeloid leukemia (CML) patients
Title of the conference
22nd Population Approach Group in Europe (PAGE) Meeting
Author(s)
Gotta V., Buclin T., Widmer N., Csajka C.
Address
Glasgow, Scotland, June 11-14, 2013
ISBN
1871-6032
Publication state
Published
Issued date
2013
Peer-reviewed
Oui
Volume
22
Series
PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe
Pages
Abstract 2904
Language
english
Abstract
Objectives: Several population pharmacokinetic (PPK) and pharmacokinetic-pharmacodynamic (PK-PD) analyses have been performed with the anticancer drug imatinib. Inspired by the approach of meta-analysis, we aimed to compare and combine results from published studies in a useful way - in particular for improving the clinical interpretation of imatinib concentration measurements in the scope of therapeutic drug monitoring (TDM).
Methods: Original PPK analyses and PK-PD studies (PK surrogate: trough concentration Cmin; PD outcomes: optimal early response and specific adverse events) were searched systematically on MEDLINE. From each identified PPK model, a predicted concentration distribution under standard dosage was derived through 1000 simulations (NONMEM), after standardizing model parameters to common covariates. A "reference range" was calculated from pooled simulated concentrations in a semi-quantitative approach (without specific weighting) over the whole dosing interval. Meta-regression summarized relationships between Cmin and optimal/suboptimal early treatment response.
Results: 9 PPK models and 6 relevant PK-PD reports in CML patients were identified. Model-based predicted median Cmin ranged from 555 to 1388 ng/ml (grand median: 870 ng/ml and inter-quartile range: 520-1390 ng/ml). The probability to achieve optimal early response was predicted to increase from 60 to 85% from 520 to 1390 ng/ml across PK-PD studies (odds ratio for doubling Cmin: 2.7). Reporting of specific adverse events was too heterogeneous to perform a regression analysis. The general frequency of anemia, rash and fluid retention increased however consistently with Cmin, but less than response probability.
Conclusions: Predicted drug exposure may differ substantially between various PPK analyses. In this review, heterogeneity was mainly attributed to 2 "outlying" models. The established reference range seems to cover the range where both good efficacy and acceptable tolerance are expected for most patients. TDM guided dose adjustment appears therefore justified for imatinib in CML patients. Its usefulness remains now to be prospectively validated in a randomized trial.
Create date
11/06/2013 10:23
Last modification date
20/08/2019 12:40
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