Obesity and drug pharmacology: a review of the influence of obesity on pharmacokinetic and pharmacodynamic parameters

ABSTRACT

Introduction: The rising prevalence of obesity confronts clinicians with dosing problems in the (extreme) overweight population. Obesity has a great impact on key organs that play a role in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, however the ultimate impact of these changes on how to adapt the dose may not always be known.

Areas covered: In this review, physiological changes associated with obesity are discussed. An overview is provided on the alterations in absorption, distribution, drug metabolism and clearance in (morbid) obesity focusing on general principles that can be extracted from pharmacokinetic studies. Also, relevant pharmacodynamic considerations in obesity are discussed.

Expert opinion: Over the last two decades, increased knowledge is generated on PK and PD in obesity. Future research should focus on filling in the knowledge gaps that remain, especially in connecting obesity-related physiological changes with changes in PK and/or PD and vice versa. Ultimately, this knowledge can be used to develop physiologically based PK and PD models on the basis of quantitative systems pharmacology principles. Moreover, efforts should focus on thorough prospective evaluation of developed model-based doses with subsequent implementation of these dosing recommendations in clinical practice.

KEYWORDS:

• Obesity
• morbid obesity
• pharmacokinetics
• pharmacodynamics
• body size descriptors
• individualized drug dosing

Article highlights

• Both gastric emptying and gut permeability are affected by obesity, however oral bioavailability seems generally unaffected in obesity or may only increase in morbid obesity (BMI > 40 mg/m²).

• Volume of distribution is influenced by many factors and its obesity related changes are therefore difficult to predict on the basis of drug properties such as lipophilicity alone.

• Impaired drug penetration in obesity is important to take into consideration, which is especially relevant antibiotics that require adequate tissue concentrations in skin or other tissues.

• While cardiac output is known to increase with obesity, the impact on liver and renal perfusion and function may vary, especially in prolonged obesity where steatohepatitis, alterations in enzyme activity and chronic kidney disease may be present.

• The ultimate influence of obesity on drug clearance seems to vary depending on multiple drug- and patient related factors including the CYP-enzymes involved, the extraction ratio, changes in liver blood flow and drug transporters and possibly also the duration of obesity.

• Despite a reported (initially) increased GFR in obese patients, renal drug clearance does not necessarily increase, which might be explained by a decline in GFR in obesity on the longer term due to a constantly elevated intra-glomerular pressure.

• Information on the pharmacodynamic changes in obesity is essential in translation of PK models into drug dosing recommendations, for example for anesthetics, antibiotics or sedative agents.

• Using quantitative systems pharmacology principles, drug dosing recommendations can be derived for obese individuals by integrating different drug-specific PK/PD and population specific (patho-)physiological information.

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Declaration of interest

R.J.M. Brüggemann declares that he has served as consultant to and has received unrestricted research grants from Astellas Pharma Inc., F2G, Gilead Sciences, Merck Sharpe and Dohme Corp., and Pfizer Inc. All payments were invoiced by the Radboud University Medical Center. The authors have no other 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 apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

This article has been republished with some minor changes in Figures 1 and 2. These changes do not impact the academic content of the article.

Additional information

Funding

This work was supported by ZonMW under grant 836041004.