Drug pharmacokinetics in the obese population: challenging common assumptions on predictors of obesity-related parameter changes

ABSTRACT

Introduction

Obesity is associated with many physiological changes. We review available evidence regarding five commonly accepted assumptions to a priori predict the impact of obesity on drug pharmacokinetics (PK).

Areas covered

The investigated assumptions are: 1) lean body weight is the preferred descriptor of clearance and dose adjustments; 2) volume of distribution increases for lipophilic, but not for hydrophilic drugs; 3) CYP-3A4 activity is suppressed and UGT activity is increased, implying decreased and increased dose requirements for substrates of these enzyme systems, respectively; 4) glomerular filtration rate is enhanced, necessitating higher doses for drugs cleared through glomerular filtration; 5) drug dosing information from obese adults can be extrapolated to obese adolescents.

Expert opinion

Available literature contradicts, or at least limits the generalizability, of all five assumptions. Clinical studies should focus on quantifying the impact of duration and severity of obesity on drug PK in adults and adolescents, and also include oral bioavailability and pharmacodynamics in these studies. Physiologically based PK approaches can be used to predict PK changes for individual drugs but can also be used to define in general terms based on patient characteristics and drug properties, when certain assumptions can or cannot be expected to be systematically accurate.

KEYWORDS:

• Clearance
• drug dosing
• obesity
• pharmacokinetics
• volume of distribution

Article highlights

• It is not justified to a priori select lean body weight as a size descriptor for inter-individual variability in clearance in obese individuals, nor does any other size descriptor qualify for this. Total body weight in a non-linear function is mostly reported as the optimal descriptor to predict clearance.

• The impact of obesity on distribution volume varies widely and cannot be predicted based solely on lipophilicity. In general, there seems a (small) increase for hydrophilic drugs, while for lipophilic drugs, there is high inter-drug variability.

• Hepatic clearance is influenced not only by changes in activity or abundance of hepatic enzymes resulting from obesity-related changes but also by changes in plasma protein binding and hepatic blood flow, with the exact influence depending on drug extraction ratios.

• Despite a possible increase in glomerular filtration rate (GFR) in obese individuals, absolute renal clearance does not necessarily increase for all drugs that are mainly eliminated by GFR, because kidney function and transporter-mediated secretion and reabsorption may also be impacted by obesity.

• Findings on clearance and dose adjustments from obese adults cannot always be extrapolated to obese adolescents, possibly due to differences in the duration of obesity and time needed for physiological changes to manifest and impact PK parameters.

Declaration of interest

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.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17425255.2022.2132931

Additional information

Funding

This paper was funded by China Scholarship Council (grant number: 201906010328).