Evaluating pharmacokinetics and dosing strategies of antibiotics and biologics in lean and obese animal models

Abstract

Obesity is a global health concern impacting over 890 million adults and poses significant challenges to healthcare systems worldwide. Despite its prevalence, our understanding of how obesity influences pharmacokinetics and drug biodisposition remains limited. Understanding how obesity affects drug disposition is crucial, as traditional dosing strategies are often based on studies conducted in non-obese individuals. This reliance can result in suboptimal therapeutic outcomes for obese patients, who may experience altered pharmacokinetics due to the physiological changes associated with increased body fat. This dissertation investigates the pharmacokinetic alterations associated with obesity, focusing on antibiotics such as cefoxitin, cefazolin, and piperacillin, along with biologics including nivolumab and recombinant human erythropoietin. By examining obesity-induced changes in the pharmacokinetics of these commonly used drugs, this research aims to determine whether current dosing regimens need to be adjusted for the obese population. In Chapter 1, the introduction provides an overview of the obesity epidemic, discusses the impact of obesity on drug pharmacokinetics, and highlights the importance of body composition in pharmacokinetics. Additionally, it covers the general pharmacokinetic profiles of cefoxitin, cefazolin, piperacillin, nivolumab, and recombinant human erythropoietin. Chapter 2 presents a fully validated LC-MS/MS method for the simultaneous quantitation of cefoxitin, cefazolin, and piperacillin in rat plasma and twelve tissues including abdominal adipose tissue, brain, heart, kidney, liver, lungs, muscle, subcutaneous adipose tissue, skin, small intestine, spinal cord, and spleen. This method demonstrates efficiency through its sensitivity and high throughput, requiring only a minimal sample volume of 5 μL for plasma and 50 – 100 μL for tissue homogenates. Building on the validated bioanalytical method presented in Chapter 2, Chapter 3 quantifies the plasma and tissue concentrations of cefoxitin, cefazolin, and piperacillin collected from lean and obese rats collected at 5, 15, 30, 45, 60, 90, and 120 minutes following intravenous administration of these antibiotics according to body weight. Comprehensive experimental data are collected, including body measurements (total body weight, body length, abdominal circumference), body composition (fat mass and lean mass), and tissue weights from both lean and obese rats. Noncompartmental analysis is performed to compare pharmacokinetics parameters between lean and obese animals. The results indicated that mg/kg dosing is required for obese animals to achieve drug exposure levels comparable to those in lean animals. A whole-body physiologically based pharmacokinetic model is then developed to describe these concentrations, integrating physiological parameters such as tissue weight and blood flow rates for both groups. This model provides a mechanistic framework that enhances our understanding of drug distribution across various tissues. The data generated from this study is anticipated to inform future translational research and support the optimization of antibiotic dosing strategies for the obese population in clinical settings. In Chapter 4, the dissertation further investigates the pharmacokinetics of biologics, specifically focusing on nivolumab and recombinant human erythropoietin using a diet-induced obese rat model. Male Long-Evans rats were fed a high-fat diet to induce obesity, with their progress monitored through various body metrics. The rats were then received nivolumab or recombinant human erythropoietin via intravenous or subcutaneous injection. The collected serum samples were analyzed using ELISA, and pharmacokinetic parameters were calculated using noncompartmental pharmacokinetics analysis. While our previous studies indicated significant differences in pharmacokinetics of human IgG in lean and obese rats, this study found no observable differences in nivolumab and recombinant human erythropoietin in pharmacokinetics between lean and obese rats. The results that mg/kg dosing of these 2 biologics is necessary for obese animals to achieve comparable drug exposure to lean animals. Further research with other biologics is needed in both preclinical and clinical settings to identify optimal dosing strategies for obese populations. Male Long-Evans rats were fed a high-fat diet to induce obesity, with their progress monitored through various body metrics. The rats then received either nivolumab or recombinant human erythropoietin via intravenous or subcutaneous injection. Serum samples were collected and analyzed using ELISA, and pharmacokinetic parameters were calculated using noncompartmental analysis. While our previous studies indicated significant pharmacokinetic differences for human IgG between lean and obese rats after intravenous and subcutaneous injection, this study found no significant differences in the pharmacokinetics of nivolumab and recombinant human erythropoietin between the two groups. These findings suggest that mg/kg dosing of nivolumab and recombinant human erythropoietin is necessary for obese animals to achieve drug exposure comparable to that of lean animals. The differing conclusions between our previous findings on human IgG and the current study also highlight that the pharmacokinetics of each biologic may vary in obese populations. Therefore, further research with other biologics currently in use is essential in both preclinical and clinical settings to establish optimal dosing strategies for obese individuals. Overall, this dissertation explores the impact of obesity on the pharmacokinetics of both small and large molecules, emphasizing the necessity for tailored dosing strategies to improve therapeutic efficacy using a diet-induced animal model. These findings aim to enhance our understanding of drug biodisposition in obese populations and provide a foundation for optimizing therapeutic approaches in this growing demographic.Ph.D.Includes bibliographical reference