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Journal article
A novel application of t-statistics to objectively assess the quality of IC50 fits for P-glycoprotein and other transporters
Pharmacology research & perspectives, v 3(1), pp 1-n/a
02 Dec 2014
PMID: 25692007
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Current USFDA and EMA guidance for drug transporter interactions is dependent on IC
50
measurements as these are utilized in determining whether a clinical interaction study is warranted. It is therefore important not only to standardize transport inhibition assay systems but also to develop uniform statistical criteria with associated probability statements for generation of robust IC
50
values, which can be easily adopted across the industry. The current work provides a quantitative examination of critical factors affecting the quality of IC
50
fits for P-gp inhibition through simulations of perfect data with randomly added error as commonly observed in the large data set collected by the P-gp IC
50
initiative. The types of errors simulated were (1) variability in replicate measures of transport activity; (2) transformations of error-contaminated transport activity data prior to IC
50
fitting (such as performed when determining an IC
50
for inhibition of P-gp based on efflux ratio); and (3) the lack of well defined “no inhibition” and “complete inhibition” plateaus. The effect of the algorithm used in fitting the inhibition curve (e.g., two or three parameter fits) was also investigated. These simulations provide strong quantitative support for the recommendations provided in Bentz et al. (2013) for the determination of IC
50
values for P-gp and demonstrate the adverse effect of data transformation prior to fitting. Furthermore, the simulations validate uniform statistical criteria for robust IC
50
fits in general, which can be easily implemented across the industry. A calibration of the
t
-statistic is provided through calculation of confidence intervals associated with the
t
-statistic.
Metrics
Details
- Title
- A novel application of t-statistics to objectively assess the quality of IC50 fits for P-glycoprotein and other transporters
- Creators
- Michael O'Connor - Drexel UniversityCaroline Lee - Research Triangle Park FoundationHarma Ellens - GlaxoSmithKlineJoe Bentz - Drexel University
- Publication Details
- Pharmacology research & perspectives, v 3(1), pp 1-n/a
- Publisher
- BlackWell Publishing Ltd
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biodiversity, Earth, and Environmental Science (BEES); Biology; [Retired Faculty]
- Web of Science ID
- WOS:000410332300012
- Scopus ID
- 2-s2.0-84989268598
- Other Identifier
- 991019168970704721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Pharmacology & Pharmacy