Deciding on success criteria for predictability of pharmacokinetic parameters from in vitro studies: an analysis based on in vivo observations

Khaled Abduljalil, Theresa Cain, Helen Humphries, Amin Rostami-Hodjegan

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Prediction accuracy of pharmacokinetic parameters is often assessed using prediction fold error, i.e., being within 2-, 3-, or n-fold of observed values. However, published studies disagree on which fold error represents an accurate prediction. In addition, "observed data" from only one clinical study are often used as the gold standard for in vitro to in vivo extrapolation (IVIVE) studies, despite data being subject to significant interstudy variability and subjective selection from various available reports. The current study involved analysis of published systemic clearance (CL) and volume of distribution at steady state (Vss) values taken from over 200 clinical studies. These parameters were obtained for 17 different drugs after intravenous administration. Data were analyzed with emphasis on the appropriateness to use a parameter value from one particular clinical study to judge the performance of IVIVE and the ability of CL and Vss values obtained from one clinical study to "predict" the same values obtained in a different clinical study using the n-fold criteria for prediction accuracy. The twofold criteria method was of interest because it is widely used in IVIVE predictions. The analysis shows that in some cases the twofold criteria method is an unreasonable expectation when the observed data are obtained from studies with small sample size. A more reasonable approach would allow prediction criteria to include clinical study information such as sample size and the variance of the parameter of interest. A method is proposed that allows the " success" criteria to be linked to the measure of variation in the observed value. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.
    Original languageEnglish
    Pages (from-to)1478-1484
    Number of pages6
    JournalDrug Metabolism and Disposition
    Volume42
    Issue number9
    DOIs
    Publication statusPublished - 2014

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