Drug Disposition in Subjects With Obesity: The Research Work of Darrell R. Abernethy

Area of Science:

• Pharmacokinetics
• Obesity Medicine
• Clinical Pharmacology

Background:

• Dr. Darrell R. Abernethy's research began in 1979 to understand drug pharmacokinetics in obesity.
• Key variables influencing drug disposition include volume of distribution (Vd) and clearance.
• Elimination half-life is a dependent variable determined by Vd and clearance.

Purpose of the Study:

• To investigate the determinants of drug distribution, elimination, and clearance in obese individuals.
• To elucidate the relationship between obesity, drug physicochemical properties, and pharmacokinetic parameters.
• To inform appropriate drug dosing strategies for patients with obesity.

Main Methods:

• Analysis of clinical studies examining drug pharmacokinetics in obese versus control groups.
• Correction for plasma protein binding to determine pharmacokinetic Vd.
• Evaluation of drug clearance in relation to lipophilicity and degree of obesity.

Main Results:

• Obesity significantly increased pharmacokinetic Vd for lipophilic drugs distributed by passive diffusion.
• Obesity had a small, variable, and non-directional effect on drug clearance (median ratio of obese/control clearance = 1.21).
• Prolonged drug half-life in obesity was primarily attributed to increased Vd, not altered clearance.

Conclusions:

• Increased Vd in obesity is the main driver of prolonged drug half-life, potentially delaying steady-state attainment and drug washout.
• In the absence of specific data, drug maintenance doses should be based on ideal body weight.
• These findings have significant implications for optimizing chronic drug therapy in individuals with obesity.