Physiologically based pharmacokinetic modeling in obesity: applications and challenges

ABSTRACT

Introduction

Rising global obesity rates pose a threat to people’s health. Obesity causes a series of pathophysiologic changes, making the response of patients with obesity to drugs different from that of nonobese, thus affecting the treatment efficacy and even leading to adverse events. Therefore, understanding obesity’s effects on pharmacokinetics is essential for the rational use of drugs in patients with obesity.

Areas covered

Articles related to physiologically based pharmacokinetic (PBPK) modeling in patients with obesity from inception to October 2023 were searched in PubMed, Embase, Web of Science and the Cochrane Library. This review outlines PBPK modeling applications in exploring factors influencing obesity’s effects on pharmacokinetics, guiding clinical drug development and evaluating and optimizing clinical use of drugs in patients with obesity.

Expert opinion

Obesity-induced pathophysiologic alterations impact drug pharmacokinetics and drug-drug interactions (DDIs), altering drug exposure. However, there is a lack of universal body size indices or quantitative pharmacology models to predict the optimal for the patients with obesity. Therefore, dosage regimens for patients with obesity must consider individual physiological and biochemical information, and clinically individualize therapeutic drug monitoring for highly variable drugs to ensure effective drug dosing and avoid adverse effects.

KEYWORDS:

• Obesity
• PBPK
• Physiologically-based pharmacokinetics
• Model-informed precision dosing
• Drug-drug interactions

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Article highlights

1. Obesity, defined as a body mass index (BMI) ≥ 30 kg/m², is a global health problem caused by a complex combination of genetic and environmental factors that impair mobility and affect mental health.

2. Physiological alterationsrelated to obesity can affect the behavior of drugs in vivo, potentially reducing their therapeutic effectiveness and altering the required dosage levels and the body’s responsiveness to them.

3. Currently, there is no universally accepted predictive model to determine the optimal dosage regimens for different classes of drugs in patients with obesity. Clinicians are advised to tailor prescriptions by assessing the physiological and biochemical characteristics of patients with obesity. For drugs with significant variability, individualized therapeutic drug monitoring strategies are recommended where feasible.

Declaration of Interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This study was supported by Natural Science Foundation of Hunan Province (grant no. 2022JJ30899) and Scientific Research Project of Hunan Provincial Administration of Traditional Chinese Medicine (grant no. C2022041).