Volume of distribution definition: A volume of distribution is the hypothetical volume of body fluid that would be required. Meaning, pronunciation, translations and examples.
Abstract
Vancomycin was the first glycopeptide antibiotic introduced into clinical practice. Despite the numerous benefits of vancomycin, clinicians have struggled to dose vancomycin successfully in obese patients to achieve a therapeutic concentration for optimal bacterial killing. Owing to the hydrophilicity of vancomycin and the increase in both adipose tissue and muscle mass associated with obesity, the volume of distribution of vancomycin in obese patients is likely to be altered compared with non-obese patients. In addition to an increase in body mass, obesity is associated with an increase in certain circulating proteins, which results in altered free serum vancomycin concentration. Another alteration that occurs in obesity is increased blood flow secondary to increased cardiac output and blood volume, resulting in increased vancomycin clearance in obese patients. Vancomycin pharmacokinetics in the obese population remain an area of much debate, one that requires continued research given the rising number of obese patients in both the USA and worldwide.
antibiotics, volume of distribution, glycopeptides, overweight
Introduction
Vancomycin was the first glycopeptide antibiotic introduced into clinical practice. First discovered in the early 1950s and produced by Streptomyces orientalis, vancomycin exhibits bactericidal killing by inhibiting Gram-positive bacterial cell wall synthesis.1 It binds a d-alanyl-d-alanine precursor that is essential for peptidoglycan cross-linking in most Gram-positive bacterial cell walls. The spectrum of activity of vancomycin includes most Gram-positive organisms, most notably methicillin-resistant Staphylococcus aureus (MRSA). However, despite the numerous benefits of vancomycin, clinicians have struggled to consistently dose vancomycin in a manner that achieves a therapeutic serum vancomycin concentration (SVC) and an AUC to MIC ratio that is optimal for bacterial killing, while minimizing adverse effects. Several studies have addressed the population pharmacokinetic parameters of vancomycin in non-obese patients and have produced numerous nomograms for dosing vancomycin.2–5 Despite the wide use of vancomycin, very few studies to date have focused on its pharmacokinetics in the obese population.
Obesity was once viewed as a minor factor in dosing medications due to the small portion of obese patients in the population. Obesity now plays a major role in drug pharmacokinetics because of the increased incidence of obesity worldwide. The WHO estimated in 2008 that 1.5 billion adults 20 years of age and older were overweight, of whom 200 million adult men and nearly 300 million women met the clinical criteria for obesity.6 Based on 2005 data, the WHO estimates that ∼60% of the world’'s population will be classified as either overweight or obese by the year 2030.7 The National Health and Examination Survey (NHANES) reported in 2010 that all states in the USA had a prevalence of obesity of >20%; 36 states had a prevalence of ≥25%, with 12 of these states having a prevalence of ≥30%.8 Based on 2005 data from the European HAPIEE (Health, Alcohol and Psychosocial factors in Eastern Europe) study, the highest incidences of obesity were found in regions of Italy, Spain, Portugal, Poland, the Czech Republic, Romania and Albania. In many European countries included in the study, the incidence of obesity was greater in females than in males which accounted for 25% of the overall incidence of obesity in the given countries.9
Clinical obesity can be defined using various techniques previously published in the literature. The most commonly utilized methods to define obesity in pharmacokinetic studies are the body mass index (BMI), body fat content as a percentage of actual body weight, and total body weight (TBW) as a percentage of ideal body weight (IBW).10–13 Other more recently defined methods utilize parameters such as the biomechanical lean body weight and predicted normal body weight (PNWT).14,15 Despite the possible benefits of these newer methods, clinical trials that have been conducted to validate them have been limited.16 The WHO classification of obesity is based on the BMI scale and is divided into three classes: obese class I (BMI 30.00–34.99 kg/m2), obese class II (BMI 35.00–39.99 kg/m2) and obese class III, which is also synonymous with the term ‘morbid obesity’ (BMI ≥40.00 kg/m2).17 Obesity can be defined as body fat content of 25%–30% of TBW (a TBW:IBW ratio of 1.25–1.3 : 1.0), while morbidly obese has been defined as TBW exceeding 200% of IBW (TBW:IBW ratio of ≥2 : 1).18 Despite the general agreement on the definition of obesity among healthcare professionals, some researchers have utilized variations of the above-mentioned criteria to define obesity and morbid obesity in various clinical trials.
Pathophysiology of obesity related to vancomycin pharmacokinetics
Obesity is often attributed to an increase in body mass due solely to an increase in adipose tissue deposition; however, obesity involves numerous physiological changes, including an increase in muscle mass and connective tissue.19 Owing to the hydrophilicity of vancomycin and the increase in both adipose tissue and muscle mass associated with obesity, the volume of distribution (V) of vancomycin in obese patients is likely to be larger than that of normal weight patients. The disconnect between TBW, IBW, adjusted body weight (AdBW) and V is likely due to water accounting for ∼30% of the content of adipose tissue; thus, hydrophilic drugs such as vancomycin are able to penetrate and distribute, to some degree, in adipose tissue, thus increasing the V.
In addition to an increase in body mass, obesity is associated with an increase in certain circulating proteins that bind to various medications, affecting the free drug concentration in the blood. In the initial study to examine the extent of vancomycin binding to circulating serum proteins, Krogstad et al.1 showed that vancomycin protein binding ranged from 44% to 82% (average of 55%) in healthy adults. In addition, vancomycin binding to serum proteins in the studied concentration range of 10–100 mg/L was not shown to be concentration dependent.1 In another study, vancomycin protein binding ranged from 27% to 62% in patients with MRSA infections.18 In that study, SVC correlated with α1-acid glycoprotein (AAG) levels, which was increased in patients with documented MRSA infection. There was no correlation, however, between SVC and serum albumin levels, which were lower in MRSA patients compared with controls.20 Like patients with MRSA infection, morbidly obese patients have been shown to have increased AAG, thus possibly increasing the percentage of protein-bound vancomycin and decreasing the percentage of free vancomycin, which is thought to be the active form of vancomycin, in serum.20–22 Conversely, other studies have shown that obese patients have increased cholesterol, triglycerides and free fatty acids; this binding may displace or prevent antibiotics from binding to the serum proteins, thus increasing free antibiotic concentration in the serum.23–25 The extent of vancomycin binding to AAG and albumin in the serum remains unclear, and thus the question remains whether circulating protein levels play a major role in vancomycin pharmacokinetics.
Another alteration that occurs in obesity is increased blood flow secondary to increased cardiac output and blood volume.26–28 Due to the hydrophilicity of vancomycin, this increase in blood flow and blood volume may play a role in increased V of vancomycin. Chagnac et al.29 observed that overweight and obese patients had an increased glomerular filtration rate and increased renal plasma flow. Renal hyperfiltration occurs through renal vasodilation, which is a compensatory mechanism to overcome the increased tubular reabsorption of sodium. The compensatory vasodilation of the afferent arterioles results in increased hydrostatic pressure in the glomerulus, which can lead to renal hypertrophy similar to that seen in diabetes patients.30 This renal hypertrophy due to obesity has been associated with a larger kidney size than that in non-obese patients.31 In addition to hypertrophy of nephrons, the increase in hydrostatic pressure within the glomerulus may cause the observed increase in renal function and glomerular filtration rate noted in obese patients.
Effects of obesity on vancomycin pharmacokinetics
Altered V in obese patients
Several factors associated with obesity may alter the V of vancomycin, thus affecting the loading dose and dosing interval recommended to achieve a therapeutic serum level. In a study utilizing single-dose kinetics of vancomycin in healthy patients under a two-compartment model, the V of vancomycin ranged from 0.49 to 1.25 L/kg TBW.1 The first study to analyse the effects of obesity on vancomycin pharmacokinetics was conducted by Blouin et al.32 in 1982. This was an uncontrolled study of six morbidly obese patients and four normal-weight patients. The morbidly obese patients were defined as subjects >90% above IBW, while the normal patients were defined as <15% over their IBW. The range of TBW in the morbidly obese patients ranged from 96.5% to 197.7% above IBW. All subjects in both groups had normal renal function with creatinine clearance (CLCR) >90 mL/min per 1.73 m2. Vancomycin was dosed based on the previously published nomogram by Moellering et al.,33 which targeted a mean SVC of 15 mg/L. Analysis revealed that the V of vancomycin in morbidly obese patients was significantly higher than that in normal-weight patients. In addition, the V of vancomycin in morbidly obese patients correlated better with TBW (0.26 ± 0.03 L/kg TBW) than with IBW (0.68 ± 0.07 L/kg IBW). In a subsequent study, which further examined the effects of obesity on vancomycin V, 230 adult subjects with normal renal function (serum creatinine ≤1.5 mg/dL) were enrolled.34 Obese subjects (defined as >20% above IBW) accounted for 47% (107 subjects) of all the subjects in the study. The subjects received 10–15 mg/kg TBW of vancomycin with a dosing interval as previously described by Rodvold et al.3 A two-compartment model was utilized in the analysis. Both TBW and percentage over lean body weight (LBW) were found to be significant and independent predictors of V (r2 = 0.814 ± 0.13, P = 0.0001, and r2 = 0.536 ± 0.094, P = 0.0001, respectively). In addition, age was found to be an independent predictor of V (r2 = 0.219 ± 0.075, P = 0.04). The authors concluded that the vancomycin pharmacokinetic parameter most affected by body weight was V. Ducharme et al.35 studied the effects of obesity on vancomycin V in 1085 sets of vancomycin serum peaks and troughs obtained from 704 patients. Patients were excluded if their serum creatinine was <0.7 mg/dL. Obese patients were defined as patients with a TBW:IBW ratio of >1.30. Multivariate analysis of variance indicated that gender, age and weight were significant and independent factors affecting V. In obese subjects, V was represented by 0.89 L/kg IBW or 0.56 L/kg TBW, while other studies, such as that by Thomson et al.,36 reported a higher V that ranged from 1.4 to 1.7 L/kg TBW. In the study by Thomson et al., in which obese patients represented 19% of the total study population, replacing TBW with IBW or LBW did not improve the fit of the population model. Based on the results of studies that have examined vancomycin pharmacokinetics, it is likely that variation in age, sex, muscle mass and protein binding play a role in determining the V of vancomycin. A summary of the studies conducted in obese and morbidly obese patients with regard to vancomycin V can be found in Table 1.
Volume of distribution (V) reported by various studies