2022
DOI: 10.1002/jcph.2093
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Drug Disposition in Subjects With Obesity: The Research Work of Darrell R. Abernethy

Abstract: In 1979, the late Dr. Darrell R. Abernethy and colleagues began a series of clinical studies aimed at understanding the pertinent determinants of drug distribution, elimination, and clearance in obesity, and how those variables are interconnected. The studies confirmed that volume of distribution (Vd) and clearance are the principal independent biological variables, which conjointly determine elimination of half‐life as a dependent variable. For drugs distributed by passive diffusion, their pharmacokinetic Vd … Show more

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Cited by 14 publications
(33 citation statements)
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“…Most body weight scalers demonstrate a nonlinear relationship between clearance and size, a relationship that is evident in both obese and lean individuals [ 1 ]. The rate of clearance increase slows as size increases; consequently dose, when expressed as per kilogram of total body weight, is invariably excessive.…”
Section: Pharmacokinetic Concepts To Determine Dosementioning
confidence: 99%
See 1 more Smart Citation
“…Most body weight scalers demonstrate a nonlinear relationship between clearance and size, a relationship that is evident in both obese and lean individuals [ 1 ]. The rate of clearance increase slows as size increases; consequently dose, when expressed as per kilogram of total body weight, is invariably excessive.…”
Section: Pharmacokinetic Concepts To Determine Dosementioning
confidence: 99%
“…Total body weight dosing in obese children contributes to dose errors because the contribution from the fat mass portion of the body composition is not acknowledged. Although it is recognized that fat mass may influence pharmacokinetic parameters such as volume of distribution (V) or clearance (CL) [ 1 ], that the effect of fat mass is drug-specific [ 1 ], that weight-based dosing is a contributor to dose inaccuracies and that obesity influences disease processes, there are few practical dose recommendations for obese children [ 2 , 3 ]. A smorgasbord of body weight scalers (e.g., total body weight, body surface area, ideal body weight, lean body mass, adjusted body weight, body mass index, fat-free mass, allometry) have been used to determine dose in the obese individual [ 4 ].…”
Section: Introductionmentioning
confidence: 99%
“…Failure to account for fat mass contributes to dosing errors. There are few practical dose recommendations for obese children [ 2 , 19 ] even though it is known that fat mass influences the volume of distribution and clearance [ 20 ], that effects from fat mass are drug-specific [ 20 ], and that dosing per kilogram (weight-based linear dosing) is a contributor to dose inaccuracies. Further, obesity can be considered an inflammatory disease that both contributes to disease processes and is sometimes consequent to disease processes.…”
Section: Size Model Foiblesmentioning
confidence: 99%
“…The difference between the linear total body weight prediction and the allometric weight prediction increases with total body weight. Other bodyweight scalers shown in Figure 3 (body surface area, fat-free mass) are also curvilinear in nature, a relationship that exists in both obese and lean individuals [ 20 ]. There is no change at any one weight where a size scaler should be changed from one to another.…”
Section: Dosing Concepts In the Childmentioning
confidence: 99%
“…The HPLC retention index has been used to explain drug uptake into specific tissues and partially explain the variability in volume of distribution. 18 LogP, the logarithm of the partition coefficient, is another widely used quantitative measure of lipophilicity, it can be measured experimentally or by way of computational methods based on molecular descriptors, which offer a fast and cost-effective way to estimate lipophilicity. 15 Like HPLC, logP measures have been found to explain a portion of the variability in the volume of distribution measures.…”
Section: What Is the Role Of The Therapeutic Window Of A Drug For Inf...mentioning
confidence: 99%