Medications and Obesity Exploring the Landscape and Advancing Comprehensive Care: Proceedings of a Workshop (2024) / Chapter Skim
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2 Current State of Pharmacokinetics and Pharmacology for Obesity
2 Current State of Pharmacokinetics and Pharmacology for Obesity
Pages 3-28
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(Ryan) • The goal of obesity treatment is optimizing health, and components should include weight reduction, improvement in metabolic parameters, body composition, muscle function, and obesity-related disease health outcomes.
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MEDICATIONS THAT AFFECT WEIGHT STATUS Donna Ryan, Pennington Biomedical Research Center, provided an overview of the biology of body weight and body composition regulation. She discussed medications approved for chronic weight management, the influence of medications for various indications on weight and body composition, and potential future approaches to obesity treatment with medications toward the goal of optimizing body composition and function.
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The weight reduction in older life is generally due to reduced lean mass rather than fat mass, which sometimes increases throughout the lifespan, Ryan noted. Menopause has not been directly associated with weight gain, but dramatic changes in body fat distribution occur, Ryan explained.
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Decreased leptin levels trigger the brain to perceive starvation, which drives CNS responses to increase food intake and decrease energy expenditure. Ryan described a lepto-centric view of body mass and weight regulation in obesity research, but she noted an increasing interest in understanding how the body regulates compartments besides body fat.
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Medications with Side Effects on Body Weight and Composition Medications approved for indications other than weight management can influence body weight and composition by producing weight loss or gain, Ryan stated (Apovian et al., 2015; Kushner and Ryan, 2014)
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Testosterone, when used to treat testosterone deficiency in men, can reduce body fat and increase lean mass. Potential Future Approaches to Obesity Treatment with Medications Ryan emphasized that treating obesity should extend beyond the goal of weight loss to optimizing body composition and function.
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She highlighted that despite this risk of fracture, the intensive lifestyle intervention group saw benefits, such as improved metabolic health and reduced health care costs. Ryan noted that emerging approaches to obesity focus on improving body composition and weight loss.
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Greenblatt highlighted close intercorrelation between percent IBW and BMI, noting that BMI reasonably correlates with total body fat measured by DEXA. Drug Effects and Distribution in Relation to Lipid Solubility Abernethy correctly hypothesized that a drug's effects and distribution are in relationship with its lipid solubility, said Greenblatt.
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Greenblatt said that volume of distribution, half-life, and clearance of water-soluble cimetidine were similar for the controls and individuals with obesity, but the volume of distribution and half-life of lipid-soluble midazolam were both threefold higher in the latter group. He added that after correcting volume of distribution for total body weight -- calculated by dividing liters distributed by kilograms of total body weight -- the increase for midazolam in people with obesity held.
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12 MEDICATIONS AND OBESITY FIGURE 2-2 A model of nonlipophilic and lipophilic drug pharmacokinetic activity in healthyweight individuals and those with obesity. NOTE: C = central compartment; P = pharmacokinetic.
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Greenblatt noted that this represents that the pharmacokinetic peripheral compartment in an individual with obesity increases disproportionately and becomes larger than the anatomic increase in body size; this is due to the selective solubility of lipophilic drugs in excess adipose tissue. Drug Clearance in Individuals with Obesity Drug clearance is the volume of blood completely cleared of drug per unit of time, explained Greenblatt.
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INCLUSION OF SUBJECTS WITH OBESITY IN DRUG DEVELOPMENT Jayabharathi Vaidyanathan, FDA Office of Clinical Pharmacology, provided an overview of clinical trials in drug development. She discussed how clinical trial data are obtained, the challenges of including individuals with obesity as a regulatory consideration in drug development, and drug
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Regulatory review of clinical pharmacology data in both investigational and new drug applications examines how intrinsic and extrinsic factors influence dose or drug exposure, safety, and efficacy. The typical drug development program consists of several clinical trials, including dedicated clinical pharmacology studies to characterize pharmacokinetics and pharmacodynamics, drug–drug interactions, and effects of various intrinsic factors and other covariates.
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For example, the clinical pharmacology review template enables review staff to conduct a structured evaluation of whether intrinsic factors require an alternative dosing regimen and/or management strategy for any particular subgroup, thus ensuring therapeutic optimization and individualization. Vaidyanathan stated that obesity has known implications related to physiological changes and corresponding effects on overall drug disposition.
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Moreover, Vaidyanathan noted limitations to extrapolating dosage adjustments from adults to adolescents who have obesity. Regulatory Considerations for Including Individuals with Obesity No specific regulatory requirement is in place to include those with obesity in clinical trials, said Vaidyanathan.
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Vaidyanathan highlighted that several initiatives are underway to promote diversity in clinical trials, including statutes and regulations that require drug developers to include various demographic information and patient subgroup analyses and present subgroup analyses for efficacy and safety. Examples of obesity-specific regulatory activities include engaging stakeholders, collaborating in regulatory research and publications, reviewing drug regulatory submissions, and publishing guidance on obesity-specific recommendations (Ramamoorthy et al., 2022; Vaidyanathan et al., 2023)
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Vaidyanathan provided additional examples of obesity-related language in drug dosing that include recommendations regarding close monitoring in such patients, consideration of using longer needles to ensure correct drug administration, dose modifications, and effects of obesity on pharmacokinetics. Opportunities to Increase Obesity-Related Information in Drug Development Vaidyanathan outlined opportunities to increase information regarding obesity in drug development and provide specific labeling recommendations.
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Vaidyanathan underscored that consistent, collective efforts from all stakeholders -- including regulatory agencies, sponsors, clinicians, scientists, and trial participants -- are needed to reduce the gap in prescribing information regarding patients with obesity. TRANSFORMATION: WHAT IS TO COME IN THE PIPELINE OF ANTI-OBESITY MEDICATIONS Ania Jastreboff, Yale School of Medicine, outlined medications in clinical trials or recently approved by FDA for obesity treatment.
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As with many NuSH-based therapies, it is a once-weekly self-injectable. In the STEP-1 trial, the average weight reduction for adults is 16.9 percent body weight, or 38 pounds, at 68 weeks (Wilding et al., 2021)
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The SURMOUNT-2 trial, which looked at tirzepatide for weight management in individuals with type 2 diabetes, demonstrated similar weight reduction in addition to improved hemoglobin A1C (Garvey et al., 2023)
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Jastreboff noted that loss of 30 percent body weight is akin to the results seen with bariatric surgery. The study found variability in weight reduction, which has been demonstrated with all forms of obesity treatments, including bariatric surgery and all AOMs.
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Jastreboff noted that in addition to weekly injectable and daily oral medications, MariTide is a GIP receptor antagonist and GLP-1 receptor agonist in a monthly injectable form that is in phase 2 of development. Obesity Treatment That Optimizes Health Now that medications have made total body weight reductions of 15, 20, or 25 percent attainable, the research and clinical focus is extending beyond "just" weight reduction; the goal of treating obesity is to improve health outcomes, Jastreboff said.
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Jastreboff commented that assessing body composition and muscle function should be included in medication trials to enable data collection across ages and sexes; metrics for preservation of muscle mass and function could be determined from these data. Higginbotham replied that FDA collects body composition data, but this is performed as a subset in the trial, and data are not collected on every participant.
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He maintained that weight loss should be accompanied by efforts to mitigate lean mass loss via resistance training and appropriate diet. Clinician Resources Chow asked about the availability of resources that instruct clinicians on how best to administer drugs known to cause weight gain or with altered pharmacokinetics in people with obesity.
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For example, an older patient taking semaglutide with an indication for cardiovascular risk reduction due to a myocardial infarction may face higher risks by discontinuing AOM treatment than an 18-year-old patient with no known heart conditions. Similarly, semaglutide for a patient with chronic kidney disease yields disease-modifying efficacy; more research is needed to understand whether this is caused solely by weight reduction or by a combination of weight reduction and other effects of the drug.
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