Normal fat mass cannot be reliably estimated in typical pharmacokinetic studies

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: Fat-free mass; Ffat; Non-linear mixed-effects modeling; Normal fat mass; Pharmacokinetic modeling; Population pharmacokinetics.

Fig. 1

Flow chart of the analytical approach

Fig. 2

Distribution of total body weight (a) and fat-free mass (b) of a randomly sampled typical study containing 30 subjects, 10 subjects for each BMI group (non-obese, obese, and morbidly obese). For the figure, subjects were summarized in 10-kg weight bands for TBW and 5-kg weight bands for FFM

Fig. 3

Median and 95% confidence intervals for Ffat in NFM on clearance for a typical study size (n = 30; in red) and a large study size (n = 10,000; in cyan). The box represents the 25th and 75th percentile. The whiskers represent the 95% confidence interval. The gray shadow represents the true value of Ffat

Fig. 4

Median and 95% confidence intervals for estimated Ffat on the volume of distribution for a typical study size (n = 30; in red) and a large study size (n = 10,000; in cyan). The box represents the 25th and 75th percentile. The whiskers represent the 95% confidence interval. The gray shadow represents the true value of Ffat

Fig. 5

Median (line) and 95% confidence intervals (shade) for estimated Ffat on clearance and volume of distribution with increasing study size where the true value of Ffat on both clearance and volume of distribution is 1. Underlying data is presented in Table S1 in the supplemental materials