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Evaluating the Relationship Between Lean Liver Volume and Fat-Free Mass

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Abstract

Background

Fat-free mass has gained wide acceptance as a scaler of the maintenance dose rate in obese patients. The choice of fat-free mass as a size scaler for the maintenance dose rate is based on its relationship with drug clearance, on the basis that only lean tissue is sufficiently metabolically active to provide capacity for elimination. For xenobiotics, the majority of biotransformation occurs in the liver and hence fat-free mass is implied to scale linearly with the component of liver that is metabolically active. The liver, like the body, can be assumed to comprise two components, lean mass and fat mass. We expect the lean liver mass (or volume) to be the component that most closely relates to drug clearance.

Objective

The objective of this study was to investigate the relationship of lean liver volume and fat-free mass.

Methods

Total liver volume and liver fat volume were measured in 100 Indian adults by computed tomography. Lean liver volume was derived as the difference between the two measurements (as liver volume − liver fat volume). Covariate modelling to describe lean liver volume, using NONMEM version 7.3, involved testing the influence of body weight, sex, body surface area and fat-free mass with or without allometric scaling (by estimating the exponent) and the influence of clinical chemistry variables.

Results

The final model did not exclude a linear relationship between lean liver volume and fat-free mass, while allometric scaling by body weight0.75 was also supported by the data. While scaling by fat-free mass, the coefficient of proportionality (i.e. lean liver volume per kg fat-free mass) was higher in female (31.25 mL) than male (25.81 mL) subjects.

Conclusions

A model to predict lean liver volume from readily available patient data was developed and evaluated. Fat-free mass plus sex was found to be the best body descriptor to scale lean liver volume. The utility of this model in scaling drug clearance and dose requirements of hepatically cleared drugs needs further exploration.

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Acknowledgements

The authors acknowledge the contribution of T.K. Ponnuswamy, B. Devanand, M. Ramanathan and S. Ramalingam for generating the LLV data. T.K. Ponnuswamy, B. Devanand and S. Ramalingam were from the PSG Institute of Medical Sciences and Research, Coimbatore, India, and M. Ramanathan was from the PSG College of Pharmacy, Coimbatore, India during the conduct of the study.

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Authors and Affiliations

  1. School of Pharmacy, University of Otago, Dunedin, New Zealand

    Jaydeep Sinha, Stephen B. Duffull & Hesham S. Al-Sallami

  2. Model Answers R&D Pty Ltd, Brisbane, QLD, Australia

    Bruce Green

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  1. Jaydeep Sinha
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Correspondence to Hesham S. Al-Sallami.

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Funding

This work required no specific funding. Jaydeep Sinha received a doctoral scholarship from the School of Pharmacy, University of Otago, New Zealand during this work.

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Jaydeep Sinha, Stephen B. Duffull, Bruce Green and Hesham S. Al-Sallami have no conflicts of interest that are directly relevant to the content of this study.

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Sinha, J., Duffull, S.B., Green, B. et al. Evaluating the Relationship Between Lean Liver Volume and Fat-Free Mass. Clin Pharmacokinet 59, 475–483 (2020). https://doi.org/10.1007/s40262-019-00824-7

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