Implications of Obesity for Drug Therapy: Limitations and Challenges

Jain, Rajul K.; Chung, Sung Kee; Jain, Lokesh; Khurana, Mona; Lau, Sandra; Lee, J E; Vaidyanathan, Jayabharathi; Zadezensky, Immo; Choe, Sangmin; Sahajwalla, Chandrahas

doi:10.1038/clpt.2011.104

Cited by 188 publications

(194 citation statements)

References 70 publications

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“…Indeed, the pathophysiological changes associated with both obesity and critical illness may have additive effects on altered pharmacokinetics (PK), although there are very limited published data on this topic (11,12). The physiological differences in obese patients include changes in regional blood flow, increased cardiac output, and increased fat and lean mass (13). These changes may alter PK and PK/pharmacodynamics (PK/PD) of antimicrobials, necessitating dosing adjustment.…”

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confidence: 99%

Effect of Obesity on the Population Pharmacokinetics of Meropenem in Critically Ill Patients

Alobaid

Wallis

Jarrett

et al. 2016

Antimicrob Agents Chemother

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e Severe pathophysiological changes in critical illness can lead to dramatically altered antimicrobial pharmacokinetics (PK). The additional effect of obesity on PK potentially increases the challenge for effective dosing. The aim of this prospective study was to describe the population PK of meropenem for a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients prescribed meropenem were recruited into the following three body mass index ( ؊1 . Higher creatinine clearance (CL CR ) was associated with a lower probability of target attainment, with BMI having little effect. Although obesity was found to be associated with an increased V 1 , dose adjustment based on CL CR appears to be more important than patient BMI.

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confidence: 99%

Effect of Obesity on the Population Pharmacokinetics of Meropenem in Critically Ill Patients

Alobaid

Wallis

Jarrett

et al. 2016

Antimicrob Agents Chemother

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“…This could be attributed to alterations in the distribution, metabolism and/or transport of the drug. Indeed, increased cytochrome P450 2E1 (CYP2E1) activity leading to the increased clearance of chlorzoxazone has been reported in obese patients (9) . Studies in genetic rodent models of obesity have reported altered expression of hepatic drug transporters and metabolic enzymes (10 -13) .…”

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confidence: 99%

Effect of a high-fat diet on the hepatic expression of nuclear receptors and their target genes: relevance to drug disposition

et al. 2015

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More than 1·4 billion individuals are overweight or obese worldwide. While complications often require therapeutic intervention, data regarding the impact of obesity on drug disposition are scarce. As the influence of diet-induced obesity on drug transport and metabolic pathways is currently unclear, the objective of the present study was to investigate the effect of high fat feeding for 13 weeks in female Sprague -Dawley rats on the hepatic expression of the nuclear receptors pregnane X receptor (PXR), constitutive androstane receptor (CAR), liver X receptor (LXR) and farnesoid X receptor (FXR) and several of their target genes. We hypothesised that high fat feeding would alter the gene expression of major hepatic transporters through a dysregulation of the expression of the nuclear receptors. The results demonstrated that, along with a significant increase in body fat and weight, a high-fat diet (HFD) induced a significant 2-fold increase in the expression of PXR as well as a 2-, 5-and 2·5-fold increase in the hepatic expression of the PXR target genes Abcc2, Abcb1a and Cyp3a2, respectively (P,0·05). The expression levels of FXR were significantly increased in rats fed a HFD in addition to the increase in the expression levels of FXR target genes Abcb11 and Abcb4. The expression levels of both LXRa and LXRb were slightly but significantly increased in rats fed a HFD, and the expression levels of their target genes Abca1 and Abcg5, but not Abcg8, were significantly increased. The expression of the nuclear receptor CAR was not significantly altered between the groups. This suggests that a HFD may induce changes in the hepatobiliary transport and metabolism of endogenous and exogenous compounds.

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“…Various physiological and pharmacokinetic parameters are altered in the obese patient, which may impact the efficacy and toxicity of antimicrobial agents. Delays in gastric emptying have been reported to occur in the obese that may affect drug absorption, although most evidence suggests this effect is not sizeable [15]. The volume of distribution (V d ), which represents the degree to which a drug distributes in plasma volume and tissues, may be increased versus lean comparators, thus resulting in lower concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…The extent to which a medication is protein-bound also affects V d , and obesity has been shown to alter lipoproteins and alpha1-acid glycoprotein [2]. Physiologic changes in the liver, including fatty infiltration and altered cytochrome P450 activity, may also impact drug metabolism [15]. Similarly, baseline renal clearance is generally increased in obesity because of concomitant increases in cardiac output and blood volume that result in elevated glomerular filtration rate, although the presence of commonly associated conditions such as hypertension may reverse this phenomenon by causing chronic renal disease [2,26].…”

Section: Discussionmentioning

confidence: 99%

Obesity Is Not Associated with Antimicrobial Treatment Failure for Intra-Abdominal Infection

Dietch

Duane

Cook

et al. 2016

Surgical Infections

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Background: Obesity and commonly associated comorbidities are known risk factors for the development of infections. However, the intensity and duration of antimicrobial treatment are rarely conditioned on body mass index (BMI). In particular, the influence of obesity on failure of antimicrobial treatment for intra-abdominal infection (IAI) remains unknown. We hypothesized that obesity is associated with recurrent infectious complications in patients treated for IAI. Methods: Five hundred eighteen patients randomized to treatment in the Surgical Infection Society Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial were evaluated. Patients were stratified by obese (BMI ‡30) versus non-obese (BMI ‡30) status. Descriptive comparisons were performed using Chi-square test, Fisher exact test, or Wilcoxon rank-sum tests as appropriate. Multivariable logistic regression using a priori selected variables was performed to assess the independent association between obesity and treatment failure in patients with IAI. Results: Overall, 198 (38.3%) of patients were obese (BMI ‡30) versus 319 (61.7%) who were non-obese. Mean antibiotic d and total hospital d were similar between both groups. Unadjusted outcomes of surgical site infection (9.1% vs. 6.9%, p = 0.36), recurrent intra-abdominal infection (16.2% vs. 13.8, p = 0.46), death (1.0% vs. 0.9%, p = 1.0), and a composite of all complications (25.3% vs. 19.8%, p = 0.14) were also similar between both groups. After controlling for appropriate demographics, comorbidities, severity of illness, treatment group, and duration of antimicrobial therapy, obesity was not independently associated with treatment failure (c-statistic: 0.64). Conclusions: Obesity is not associated with antimicrobial treatment failure among patients with IAI. These results suggest that obesity may not independently influence the need for longer duration of antimicrobial therapy in treatment of IAI versus non-obese patients.

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Implications of Obesity for Drug Therapy: Limitations and Challenges

Cited by 188 publications

References 70 publications

Effect of Obesity on the Population Pharmacokinetics of Meropenem in Critically Ill Patients

Effect of Obesity on the Population Pharmacokinetics of Meropenem in Critically Ill Patients

Effect of a high-fat diet on the hepatic expression of nuclear receptors and their target genes: relevance to drug disposition

Obesity Is Not Associated with Antimicrobial Treatment Failure for Intra-Abdominal Infection

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