Comments on the Statistical Analysis of Toxicokinetic Studies
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0092-86 15/97 Copyright 0 1997 Drug Information Association Inc.
COMMENTS ON THE STATISTICAL ANALYSIS OF TOXICOKINETIC STUDIES HARRYMAGER Head, Preclinical and Clinical Biostatistics
GERNOTGOLLER Department of Preclinical Pharmacokinetics BAYER AG, Centre of Drug Research, Wuppertal, Germany
This paper provides a brief review of the properties shared by chemical kinetics, clinical pharmacokinetics, and toxicokinetics and on where they diffeel: The special situation of toxicokinetics and some methods for estimating secondary pharmacokinetic parameters are discussed. The focus is on the application of resampling techniques to toxicokinetic studies and a comparison to the classical approaches. In many cases resampling techniques enjoy the advantage of being easy to perform and easy to adapt to new designs, and there is generally no need to f i t the data to certain distributions. Complicated theoretical calculations can be circumvented and new methods, for example, of area under the data (AUD) calculation, may be incorporated without substantial effort. Two resampling techniques, the pseudo-profile based bootstrap and the pooled data bootstrap, are outlined. One of the appealing features of the pseudo-profile based bootstrap is the possibility of estimating summary statistics on the basis of individual secondary pharmacokinetic parameter estimates. Key Words: Toxicokinetics; Destructive sampling; Sparse data; Resampling techniques
INTRODUCTION IN CLINICAL PHASE I studies concentration-time courses are generally derived on an intraindividual basis, that is, the aim is to get for each subject enrolled in the trial a complete drug profile. This is due to the fact that individual biological peculiarities give rise to different curves across subjects. In contrast, this approach is often not feasible in toxicity related studies due to experimental restrictions. Quite often, only one measurement per animal or organ can be taken. The consequence is that biostatistical analyses must be adapted to these design limitations.
THE DEFINITION OF TOXICOKINETICS Toxicokinetics as a technical term has been defined in a number of different ways and there is no common understanding of what “toxicokinetics” actually comprises. Although all Based on a presentation given at the DIA Workshop “Statistical Methodology in Non-clinical and Toxicological Studies,” March 25-27, 1996, Bruges, Belgium. Reprint address: Harry Mager, Head, Preclinical and Clinical Biostatistics, BAYER AG, Centre of Drug Research, Aprather Weg, D-42096 Wuppertal, Germany.
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Harp Mager and Gemor Giiller
definitions include toxicological or safety aspects, they may be distinctly different with regard to the populations considered, the type of substances aimed at, and the main objectives. For example, many authors, especially prior to the nineties, restricted the term "toxicokinetics" de facto to 'pharmacokinetics of a toxin' (1). Others extended this definition to all substances entering toxicity testing, especially in the pharmaceutical industry (2.3). S
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