Mechanisms of obesity-induced changes in drug pharmacokinetics

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Abstract Title: Mechanisms of obesity-induced changes in drug pharmacokinetics Biodisposition profile (pharmacokinetics) of a drug in an individual is governed by drug properties and subject characteristics. The underlying mechanisms of obesity-induced changes in drug pharmacokinetics have not been sufficiently studied. Beyond all, obesity is characterized by an alteration of body composition (i.e., disproportional increase in fat mass). The prevalence of obesity in the United States nearly doubled from the early 1960s, and over 1.6 billion people worldwide are considered obese or overweight. Little is known regarding the effects of obesity on biodisposition of various drug classes, and no consensus on the best dosing strategy for drugs in obese patients has been established. Attaining therapeutic drug concentration at target sites is required for successful therapeutic outcome. However, our preliminary study in bariatric surgery patients found subtherapeutic antibiotic concentration in the subcutaneous adipose tissue at the time of closure; and similar results were reported by other investigators. This inadequate drug exposure might result in therapy failure in a specific patient and lead to antibiotic resistance harming the population as a whole. Consequently, dosing strategies for antibiotics in obese patients are currently suboptimal, which might lead to treatment failure. Our data also indicate that pharmacokinetics of antibodies (Immunoglobulin G) is also affected by obesity, which may lead to decreased efficacy and increased toxicity of treatment. We hypothesize that obesity significantly affects the biodisposition of small-molecule drugs and protein therapeutics. Further, combining measurements of body composition and pharmacokinetic modeling can be used for predicting drug exposure in obese patients and facilitate drug selection and optimization of drug dosing in the obese population. The overall goal of this proposal is to determine how obesity affects pharmacokinetics of beta- lactam antibiotics and antibodies and to develop mathematical models for predicting drug biodisposition in obese patients. To achieve this we will: 1) Investigate how obesity affects the pharmacokinetics of small- molecule drugs using cefoxitin and piperacillin/tazobactam combination in obese human patients, and investigate the mechanisms of these changes in a preclinical model of obesity; 2) Investigate how obesity affects the pharmacokinetics of immunoglobulin G (IgG) (a protein therapeutic and skeleton for many monoclonal antibodies) in obese human patients, and investigate the mechanisms of obesity-induced changes in pharmacokinetics of IgG and other proteins in a preclinical model. Clinical and preclinical studies will be accompanied by measurement of the body composition; and translational mathematical models will be developed for predicting obesity-induced changes in pharmacokinetics of these and other drugs in humans. The proposed research will fill critical knowledge gaps in understanding how obesity affects the biodisposition of drugs and how drug selection and dose optimization can be achieved in obese patients. We anticipate this study will have a substantial and widespread significance on drug selection and dosing practices for various drugs and will improve efficacy and safety of therapy in obese population.