Spotlight commentary: Changes in pharmacokinetics following significant weight loss

Abstract

Obesity is associated with detrimental metabolic, mechanical and psychological outcomes, leading to diminished qualify of life and reduced lifespan. Whilst lifestyle modifications, including diet and physical activity, remain essential for managing obesity management, many patients with obesity require additional interventions for effective treatment. These include anti-obesity medicines (e.g., GLP-1 receptor agonists) and/or bariatric surgery.

Research investigating changes in pharmacokinetic (PK) and pharmacodynamic (PD) properties following significant weight loss has predominately focused on patients undergoing bariatric surgery. However, with the increasing availability and efficacy of pharmacological anti-obesity interventions, there is a need to highlight the potential impact of significant weight loss on drug dose requirements. This commentary turns the spotlight to the potential of significant weight loss and subsequent changes in drug dose requirements, associated with non-surgical anti-obesity interventions. Spotlight commentaries were introduced to BJCP in 2019 and aim to ‘identify emerging themes—pulling together related content that has recently been published in the Journal [and] placing this in the context of contemporaneous work in other journals’.¹

Currently, six medications are approved in several countries for treating non-syndromic obesity as adjuncts to lifestyle modifications: orlistat, phentermine, naltrexone/bupropion, liraglutide, semaglutide and tirzepatide.² Among these, tirzepatide has shown the highest efficacy, achieving a median weight loss of 22.5% in one study; comparable to that of some bariatric surgery approaches.² In comparison, the GLP-1 receptor agonist semaglutide has been reported to induce a median loss of 15.8%.³ Bariatric surgery, however, remains associated with greater weight loss, with rates up to 71%.⁴

Obesity and significant weight loss profoundly influence drug pharmacology. The use of total body weight to adjust drug doses in the obese can potentially result in drug toxicity. Ideal body weight (IBW) and other body size descriptors (e.g., body surface area) have shown to be more cautious alternatives to scale drug doses in the obese. However, an accurate scaler requires understanding of the effect of obesity, and significant weight loss, on drug kinetics. Recent work by Busse et al., published in BJCP, and O'Hanlon et al. has demonstrated the role of obesity and body composition on clearance (CL) and volume of distribution (V) and to a lesser extent gastrointestinal transit time and absorption.^{5, 6}

Several studies have described the changes in pharmacokinetics and dose requirements following significant and rapid weight loss in the context of bariatric procedures. For instance, Colin et al. demonstrated that fat-free mass (FFM)-based dosing in patients taking moxifloxacin at least 6 months post-bariatric surgery, resulted in a better attainment of target concentration compared with weight-based dosing.⁷

The relationship between drug dose requirements and weight stem from the high correlation between drug clearance and body size and composition. Clearance (CL), which determines the maintenance dose, is usually scaled to an appropriate descriptor of body size. Total body weight is the usual size scaler used due to a reasonable correlation to drug metabolism and its ease of measurement. However, for the majority of drugs, drug elimination usually occurs in the lean (i.e., fat-free) portion of the body; thus, scaling CL by total body weight in obese patients will likely result in overestimation of CL and subsequently overestimation of maintenance dose.

These issues necessitated the use of other body size scalers that are expected to correlate better with CL in obese individuals. A notable example is FFM also known as lean-body weight. FFM, which accounts for body composition by excluding all body fat, has become the preferred body size descriptor in population pharmacokinetic studies.^{8, 9} Sinha et al. provided a comprehensive overview and comparison of FFM measurement and prediction methods.¹⁰

The effect of obesity and significant weight loss on drug distribution volume (V) is important particularly in understanding loading dose requirements. In obese patients, V of highly lipophilic drugs (e.g., some β-adrenoceptor blockers, sufentanil and diazepam) tends to be greater, whilst their elimination half-life is prolonged, which may require dosage adjustments either in case of rapid weight gain or, conversely, following significant and acute weight loss.¹¹

Overall, substantial changes in drugs' kinetics can manifest following significant weight loss, with variations depending on the type of weight loss intervention, be it surgical or pharmacological. Thus, altering therapy and drug dosage require careful consideration of the patient's individual response and needs.¹² In principle, adipose mass would be an appropriate descriptor of dug V for moderate to highly lipophilic drugs, whilst lean mass (e.g., FFM) would be an appropriate descriptor of drug CL and can guide chronic dosing.

Although there is guidance available regarding the anticipated changes in drug kinetics after bariatric surgery, there is a notable absence of studies discussing the changes in pharmacokinetics following the significant, yet slower and reversible, weight loss induced by medications.

Dose optimisation can be challenging in extremely obese individuals and those with rapid and significant weight loss. For drugs with a narrow therapeutic range, therapeutic drug monitoring and personalized dosing might be necessary.¹³ Additionally, advancing knowledge in population PK, PKPD and physiologically based pharmacokinetic (PBPK) modelling can improve clinical guidance. Two recent articles demonstrated the use of PBPK models to predict PK and guide dosing in obese patients. Machado et al. developed a scaled PBPK model of semaglutide, highlighting its potential to predict semaglutide PK in obese children and adolescents.¹⁴ Martins et al. presented a PBPK model of ceftaroline and daptomycin, adapting it to account for PK changes in obese individuals.¹⁵

Understanding the influence of excess fat, body composition and significant weight changes on PK, and potentially PD, parameters can assist in optimizing dosage for this patient population. This is particularly relevant as the number of morbidly obese individuals and those experiencing significant weight loss following either surgery or, increasingly, anti-obesity medications continues to grow. Further well-designed PK, PKPD and PBPK studies are needed to address the specific challenges discussed in this commentary.

The authors declare no conflict of interest.