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Age-Related Change in Hepatic Clearance Inferred from Multiple Population Pharmacokinetic Studies: Comparison with Renal Clearance and Their Associations with Organ Weight and Blood Flow

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Abstract

Objective

This study aimed to examine the magnitude of age-related change in hepatic clearance by integrating the data of multiple drugs and to compare this with renal clearance, considering associations with age-related changes in organ weight and blood flow.

Methods

The results of multiple population pharmacokinetic analyses that detected age-related clearance changes in hepatically eliminated drugs were collected. The relationship between hepatic clearance of the unbound drug and age was then analyzed using the nonlinear least-squares method, adjusting for interdrug differences. The obtained change in hepatic clearance was compared with age-related changes in liver weight and hepatic blood flow in Japanese and Westerners. For comparison, the changes in renal clearance were analyzed similarly.

Results

In total, 18 drugs were analyzed. The hepatic unbound clearance decreased by 32% at age 80 years and by 40% at age 90 years, compared with age 40 years, suggesting that it decreased by 0.80% per year with aging. The rate of the decrease was consistent with decreases in hepatic weight per person or blood flow per person, regardless of ethnicity and sex. Since age-related change in body weight varied somewhat by sex or ethnicity, hepatic weight per body weight was less consistent to account for age-related change in hepatic clearance. As for an index of renal clearance, the changes in inulin clearance with age were similar to those in renal blood flow, with a decrease of 0.97% per year from the age of 40 years.

Conclusions

Hepatic clearance consistently decreased by 0.80% per year from the age of 40 years, with aging for multiple drugs analyzed in this study. Changes in organ weight and blood flow are considered to be primarily responsible for the age-related changes in hepatic and renal clearance.

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Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8675, Japan

    Kuretake Soejima, Hiromi Sato & Akihiro Hisaka

  2. Bristol-Myers Squibb K.K., 6-5-1 Nishishinjuku, Shinjuku-ku, Tokyo, 163-1328, Japan

    Kuretake Soejima

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  1. Kuretake Soejima
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  2. Hiromi Sato
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Correspondence to Akihiro Hisaka.

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Funding

This study was partly supported by AMED under Grant number JP20mk0101159.

Conflict of interest

Kuretake Soejima is an employee of Bristol-Myers Squibb K.K., however Bristol-Myers Squibb K.K. was not involved in the analysis of this study. Hiromi Sato and Akihiro Hisaka have no conflicts of interest to declare.

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KS and AH designed the study; KS collected and analyzed the data; and all authors performed the research and wrote the manuscript.

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Soejima, K., Sato, H. & Hisaka, A. Age-Related Change in Hepatic Clearance Inferred from Multiple Population Pharmacokinetic Studies: Comparison with Renal Clearance and Their Associations with Organ Weight and Blood Flow. Clin Pharmacokinet 61, 295–305 (2022). https://doi.org/10.1007/s40262-021-01069-z

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