Normal fat mass cannot be reliably estimated in typical pharmacokinetic studies
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PHARMACOKINETICS AND DISPOSITION
Normal fat mass cannot be reliably estimated in typical pharmacokinetic studies Roeland E. Wasmann 1
&
Elin M. Svensson 1,2 & Stein J. Schalkwijk 1 & Roger J. Brüggemann 1 & Rob ter Heine 1
Received: 28 May 2020 / Accepted: 9 November 2020 # The Author(s) 2020
Abstract Purpose An influential covariate for pharmacokinetics is (body) size. Recently, the method of estimation of normal fat mass (NFM) has been advocated. Here, the relative contribution of fat mass, estimated as a fraction fat (Ffat), is used to explain differences in pharmacokinetic parameters. This concept is more and more applied. However, it remains unclear whether NFM can be reliably estimated in these typical studies. Methods We performed an evaluation of the reliability of NFM estimation in a typical study size (n = 30), otherwise best-case scenario, by means of a pharmacokinetic simulation study. Several values of Ffat were investigated. Results In a typical pharmacokinetic study, high imprecision was observed for NFM parameter estimates over a range of scenarios. For example, in a scenario where the true value of Ffat on clearance was 0.5, we found a 95% confidence interval of − 0.1 to 2.1, demonstrating a low precision. The implications for practice are that one could conclude that fat-free mass best describes the relationship of the pharmacokinetics with body size, while the true relationship was between fat-free mass and total body weight. Consequently, this could lead to incorrect extrapolation of pharmacokinetics to extreme body sizes. Conclusion In typical pharmacokinetic studies, NFM should be used with caution because the Ffat estimates have low precision. The estimation of Ffat should always be preceded by careful study design evaluation before planning a study, to ensure that the design and sample size is sufficient to apply this potentially useful methodology. Keywords Normal fat mass . Ffat . Fat-free mass . Population pharmacokinetics . Pharmacokinetic modeling . Non-linear mixed-effects modeling
Introduction Like humans, body size descriptors come in many shapes, with total body weight (TBW) and fat-free mass (FFM) currently being most accepted in the pharmacometric community [1]. Choosing correct size descriptors, which account for the presence of peripheral fat tissue, may be especially important when dosing a drug with a narrow therapeutic index (i.e., aminoglycosides), especially in populations with extreme body size. It has been argued that “traditional” descriptors * Roeland E. Wasmann [email protected] 1
Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Geert Grooteplein-Zuid 10, 6500 HB Nijmegen, The Netherlands
2
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
are not adequate to account for the (relative) importance of peripheral fat tissue to describe pharmacokinetic changes with increasing body size. It assumes that the pharmacokinetic parameter of interest is related to either TBW or FFM. Rec
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