It is estimated by 2010, 40% of the US adult population will be identified as obese. This article will provide a review of the impact of obesity on the pharmacokinetics of medications.
The Centers for Disease Control and Prevention (CDC) reported in 2002 that 30% of the US population aged >20 years was obese.1 It is estimated that by 2010, 40% of the US adult population will be obese.2
Obesity increases the risk of multiple disease states including hypertension, diabetes mellitus, and coronary artery disease.2 The comorbidities frequently associated with obesity result in the need for numerous medications to manage these conditions.
Obesity alters the disposition of drugs in the body (pharmacokinetics), which should be considered when prescribing medications in this patient population. Failure to adjust doses in obesity may result either in therapeutic failure or increased toxicity.
Classifications of Body Size
In characterizing body size and habitus, it is important to use a descriptive body mass measurement that will be reflective of the severity of obesity and have some relationship to the level of risk for morbidity associated with obesity.
The CDC uses body mass index (BMI) categories in determining the degree of obesity in individuals.1 Calculation of BMI is easy to compute with data that is readily assessable (height in meters and weight in kilograms). The classification is well defined. Obesity is defined by the CDC as a BMI of >30 kg/m2, and morbid obesity is defined as a BMI of >40 kg/m2.1 However, this value is not gender specific and does not discriminate adipose tissue mass from muscle mass. Body mass index may not provide an accurate measure of body habitus in individuals with larger proportions of muscle mass to adipose tissue mass.3
Figure 1: Salazar-Corcoran Equation.
Body surface area (BSA) also is a classification of body size (Figure 1). Calculating body surface area involves the use of body weight and height. Two formulas are commonly used to calculate body surface area: the DuBois and Mosteller equations. DuBois initially developed the body surface area equation from nine individuals and estimated body surface area by assuming that anatomically, bodies were equally symmetrical.4 Mostellers equation was derived from revising prior body surface area equations, providing a convenient formula allowing for quick calculations.5 Although body surface area is the formula of choice when dosing anti-neoplastic medications, it is not particularly accurate when dosing these medications in obesity.6 Further study and possible adjustment of the body surface area equation is warranted to provide more predictable cytotoxicity when dosing anti-neoplastic medications in the obese population.
Ideal body weight is a calculated estimate of lean body mass and is corrected for gender and height. It was originally developed in 1943, and related body size to risk of mortality. Devine went on to further develop ideal body weight calculations (Table 1) for men and women for medical purposes.7,8 These equations are commonly used today for dosing of specific medications such as acyclovir.9
This estimation may be beneficial since lean body mass is not readily measured in obesity. However, obese individuals may have up to a 20%-55% increase in lean body mass (fat-free mass) compared to those that are not obese.10 Thus, ideal body weight may be underestimated in the obese when using the Devine equation.
Some medications may incompletely distribute into adipose tissue and require an adjusted weight for more accurate dosing. An adjusted, or dosing weight, is calculated to account for obese patients exceeding >125% of their ideal body weight.9,11,12 When dosing certain medications such as aminoglycosides, a dosing weight correction factor (DWCF) is used to account for increased body weight. It appears that fat distribution of aminoglycosides is incomplete, and 40% of the drug is estimated to distribute into adipose tissue.13-15 This explains why a dosing weight correction factor of 0.4 generally is used for all aminoglycoside dosing in obesity.11-15
ABW=actual body weight, IBW=ideal body weight.
Pharmacokinetic Factors and Obesity
Identifying the correct dose to use in patients with increased body size often is difficult and, in many cases, ill defined. Merely doubling medication dosages in obese and morbidly obese patients to account for the increase in body habitus is not optimal in most cases.
In general, the physiochemical properties of a particular medication may provide information regarding the need for dose adjustment due to obesity. The fate of a medication relies on four pharmacokinetic properties: absorption, distribution, metabolism, and elimination (A,D,M,E).9,11,12 Therapeutic drug concentrations may become altered secondary to physiologic changes that occur in obesity. To provide further information on this topic, the impact of obesity on pharmacokinetics will be discussed.
Data on the effects of drug absorption and obesity is limited. Changes in absorption would be predicted in obesity due to increased body surface area and increased cardiac output, thus leading to increased gut perfusion.16,17 However, one study examining the bioavailability of propranolol in obese versus nonobese individuals showed no difference.18 Despite the theoretical rationale for altered absorption in obesity, there is no difference when comparing drug absorption in obese versus nonobese patients.9,12,19
The volume of distribution (Vd) of drugs may be altered in obese patients. Obesity results in increased adipose tissue mass, which can influence medications with lipophilic properties.9,12,16,20 Increased organ mass, lean body mass, and blood volume in obesity also can affect hydrophilic medications.9,11,19 The result of these physiologic changes in obesity can influence the volume of distribution of medications, potentially leading to sub- or supra-therapeutic concentrations.
Aminoglycosides are hydrophilic antibiotics commonly used for compound extremity fractures, osteomyelitis, and severe soft-tissue infections. The need for dosing adjustment in obesity has been established in gentamicin, tobramycin, and amikacin.9,13-15
Aminoglycosides distribute primarily into the intravascular space and only moderately into the interstitial space. Therefore, aminoglycosides typically display a slightly larger volume of distribution (in liters) in obese patients than in lean patients.
When dosing aminoglycosides using actual body weight in obesity, this may result in supratherapeutic serum concentrations that may result in increased exposure of concentrations, leading to an elevated risk for nephrotoxicity and ototoxicity in obese individuals.11,12,14 To prevent overdosing of aminoglycosides in obesity, a dosing weight correction factor of 0.4 is used to account for the altered volume of distribution.13-15
One example of a highly lipophilic intravenous anesthesia medication is propofol. It is rapidly distributed systemically and into adipose tissue. The Vd (L/kg), clearance (mL/min), and half life (hours) were all found to be similar in obese patients versus nonobese patients.20,21 Therefore actual body weight can be used when dosing in obese and non-obese patients.16,20,21
Following orthopedic surgery, enoxaparin or other low-molecular weight heparins frequently are prescribed for thromboprophylaxis. The question remains whether higher doses are needed in obesity to account for decreased subcutaneous (SC) absorption and increased Vd. Currently, the recommended dose of enoxaparin in obese patients is similar to that used for nonobese patients: enoxaparin 30 mg subcutaneously every 12 hours.22
Data is sparse concerning the most safe and effective dose to use following orthopedic surgery. One study reported results of two dosing strategies in patients following bariatric surgery.23 Although this study did not address pharmacokinetic alterations, dosing of enoxaparin 40 mg subcutaneously every 12 hours resulted in fewer thromboembolic events postoperatively when compared to enoxaparin 30 mg subcutaneous every 12 hours in morbidly obese patients.23 However, additional studies are needed to further support the superiority of dosing enoxaparin 40 mg subcutaneously every 12 hours in morbidly obese patients.
Fondaparinux is a selective inhibitor of factor Xa, which is in a new class of antithrombotics. Patients who received prophylaxis with fondaparinux were found to have a lower incidence of a venous thromboembolic events following major knee surgery when compared to enoxaparin.24 Because this is a newer antithrombotic agent, limited data is available for dosing in obese patients. Current dosing recommendations exist, based on pharmacokinetic results from Phase II clinical trials. Fondaparinux dosing for treatment of deep venous thromboembolism (DVT) or pulmonary embolism (PE) in patients weighing >100 kg, is adjusted to 10 mg subcutaneously daily.25,26 Future studies are warranted to confirm this dosing strategy and the relative efficacy in obese individuals.
Volume of distribution not only is affected by the amount of adipose tissue, but also by the amount of free drug not bound to plasma proteins. Obesity has been shown to correlate with increased concentrations of some of the major plasma proteins including alpha-1 acid glycoprotein and lipoproteins.9,11,12 Alpha-1 acid glycoprotein binds primarily to alkaline drugs such as clindamycin and propranolol, whereas serum lipoproteins (including triglycerides, cholesterol, and free fatty acids) bind primarily to albumin.9,11,12 Albumin concentrations have not been shown to be altered in obesity. Although alterations in plasma proteins have been observed, the net effect of drug concentrations available for tissue distribution does not appear to be significant.
Changes in hepatic clearance of various medications may be due to alterations in Phase I (oxidation, reduction, and hydrolysis) and Phase II (conjugation by sulfation or glucuronidation) reactions within the liver. Phase I reactions have been observed to be unchanged or increased in obesity.27 Antibiotics including clindamycin and metronidazole are metabolized via Phase I reactions and may be affected by obesity.28
Obesity also has been shown to increase Phase II drug biotransformation.27 Medications including lorazepam and oxazepam are metabolized by conjugation.29 Increased metabolism of these medications may result in suboptimal serum concentrations in obesity, which may lead to inadequate sedation.
Fatty infiltration of the liver may occur in obese patients, however changes in liver function tests are not routinely seen.11,12 In situations where fatty liver compromises hepatic function, elevations in plasma half-life and volume of distribution, as well as a decrease in drug clearance would be anticipated secondary to physiologic alterations of the liver.
Glomerular filtration rate (GFR) can be estimated by calculating the creatinine clearance (ClCr) to predict drug elimination.9,10,12 The clearance of many renally eliminated drugs correlates with ClCr.9-12 Alterations in ClCr have been observed in obese patients versus lean patients. The use of conventional ClCr equations may be inaccurate in obese patients.
Overestimation or underestimation of clearance can occur in obesity when considering actual body weight versus ideal body weight, respectively.9,11,12 The Cockcroft-Gault equation is commonly used to calculate glomerular filtration rate in lean patients, however its use in obesity is questionable due to the disparity between muscle mass and body weight ratio observed in obesity.30
The Salazar-Corcoran equation takes into account multiple factors to provide a better estimation of ClCr in obesity including serum creatinine, gender, actual weight, age, and height.10 This study demonstrated a 24% increase in ClCr in obese individuals, in addition to an increased rate of plasma creatinine excretion in the urine. This may relate to physiologic changes (increased organ size, increased blood volume to kidneys) observed in obesity.9-12 However, the formula is complicated and is not a particularly practical equation to use for quick reference (Figure 2).
Figure 2: Salazar-Corcoran Equation.
Vancomycin is an antibiotic commonly used for treatment of osteomyelitis and methicillin-resistant Staphylococcus aureus (MRSA) infections, and requires dosage adjustment for renal function. Comparison of values for volume of distribution and total body clearance for vancomycin were studied in morbidly obese patients versus normal weight patients.31 Mean values for Vd (in liters) were not significantly different in the morbidly obese patients versus normal weight patients when accounting for total body weight (6.4±3.2 and 7.7±2.2 L, respectively). However, a higher value for total body clearance of vancomycin was observed in morbidly obese patients versus normal weight patients (187.50 and 80.78 mL/min respectively).31
Another study also compared pharmacokinetic changes of vancomycin in morbidly obese patients versus normal weight patients.32 Shorter half lives of vancomycin were observed in morbidly obese patients (3.3 versus 7.2 hours respectively). Due to similar values for Vd and an increased clearance observed in obese and normal weight patients, initial dosing of vancomycin in obesity (with normal renal function) should consist of either 15 mg/kg of actual body weight intravenous (IV) every 12 hours, or 10 mg/kg of actual body weight IV every 8 hours.32
Although some medications have established dosing adjustments for obesity (Table 2), it remains unknown for the majority of medications if dosing adjustment is warranted. It is important to remember dosage adjustments may not be as simple as doubling an antibiotic dose because a patient is morbidly obese. Individualizing drug dosing is imperative in the obese, postoperative patient to ensure they simultaneously have therapeutic serum concentrations without drug toxicity.
Much of what has been learned from studies in obese patients is that the pharmacokinetic alterations of medications are variable. Broad application of dosing guidelines even among medications within the same therapeutic class is likely not appropriate.
An increased emphasis in researching the effects of obesity on the fate of medications is of paramount importance as the obese population grows. Practitioners should use caution and be vigilant in monitoring pharmacotherapy in obese individuals.
| The Bottom Line |
- Therapeutic serum concentrations may become altered secondary to physiologic changes that occur in obesity.
- When dosing specific medications, individualization of drug dosing may provide optimal drug concentrations in obesity.
- Understanding the impact of obesity on the disposition of a medication from absorption through elimination can provide further guidance on specific dosing considerations in obesity.
- Optimal drug dosing is paramount in the obese, surgical patient, to ensure therapeutic drug concentrations and avoid drug toxicities.
- Overweight and obesity: home. Department of Health and Human Services: centers for Disease Control and Prevention. Accessed at: http://www.cdc.gov/nccdphp/dnpa/obesity/index.htm. Updated 2005 Aug 30. Accessed September 20, 2005.
- Polk, SL. Definitions and demographics of obesity: diagnosis and risk factors. Anesthesiol Clin North America. 2005; 23:397-403.
- Green B, Duffull SB. What is the best descriptor to use for pharmacokinetic studies in the obese? Br J Clin Pharmacol. 2004; 58:119-133.
- DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med. 1916; 17:863-871.
- Mosteller A. Simplified calculation of body surface area. N Engl J Med. 1987; 317:1098.
- Loos WJ, de Jongh FE, Sparreboom A, et al. Evaluation of an alternate dosing strategy for cisplatin in patients with extreme body surface area values. J Clin Oncol. 2006; 24:1499-1506.
- Devine BJ. Gentamicin therapy. Drug Intelligence & Clinical Pharmacy. 1974; 8:650-655.
- Pai MP, Paloucek FP. The origin of the ideal body weight equations. Annals of Pharmacotherapy. 2000; 34:1066-1069.
- Wurtz, R, Itokazu G, Rodvold K. Antimicrobial dosing in obese patients. Clin Infect Dis. 1997; 25:112-118.
- Salazar DE, Corcoran GB. Predicting creatinine clearance and renal drug clearance in obese patients from estimated fat-free body mass. Am J Med. 1988; 84:1053--1060.
- Blouin RA, Warren GW. Pharmacokinetic considerations in obesity. J Pharm Sci. 1999; 88:1-7.
- Cheymol G. Effects of obesity on pharmacokinetics implications for drug therapy. Clin Pharmacokinet. 2000; 39:215-231.
- Leader WG, Tsubaki T, Chandler MHH. Creatinine-clearance estimates for predicting gentamicin pharmacokinetic values in obese patients. Am J Hosp Pharm. 1994; 51:2125-2130.
- Corcoran GB, Salazar DE, Schentag JJ. Excessive aminoglycoside nephrotoxicity in obese patients. Am J Med. 1988; 85:279.
- Blouin RA, Brouwer KL, Record KE, Griffen WO Jr, Plezia PM, John W. Amikacin pharmacokinetics in morbidly obese patients undergoing gastric-bypass surgery. Clinical Pharmacy. 1985; 4:70-72.
- Adams JP, Murphy PG. Obesity in anaesthesia and intensive care. Br J Anaesth. 2000; 85:91-108.
- Wisen O, Hellstrom PM. Gastrointestinal motility in obesity. J Intern Med. 1995; 273:411-418.
- Bowman SL, Hudson SA, Simpson G, Munro JF, Clements JA. A comparison of the pharmacokinetics of propranolol in obese and normal volunteers. Br J Clin Pharmacol. 1986; 21:529-532.
- Erstad BL. Dosing of medications in morbidly obese patients in the intensive care unit setting. Intensive Care Med. 2004; 30:18-32.
- Casati A, Putzu M. Anesthesia in the obese patient: pharmacokinetic considerations. J Clin Anesth. 2005; 17:134-145.
- Servin F, Farinotti R, Haberer JP, Desmonts JM. Propofol infusion for maintenance of anesthesia in morbidly obese patients receiving nitrous oxide. A clinical and pharmacokinetic study. Anesthesiology. 1993; 78:657-665.
- Enoxaparin sodium (Lovenox). Package Insert. Bridgewater, NJ: Aventis Pharmaceuticals Inc; 2005.
- Scholten DJ, Hoedema RM, Scholten SE. A comparison of two different prophylactic dose regimens of low molecular weight heparin in bariatric surgery. Obes Surg. 2002; 12:19-24.
- Bauer KA, Eriksson BI, Lassen MR, Turpie AG. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med. 2001; 345:1305-1310.
- Fondaparinux sodium (Arixtra) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2005.
- Treatment of deep venous thrombosis with a novel synthetic compound (SR91017A/ORG31540) with pure anti factor Xa activity: A phase II evaluation. The Rembrandt Investigators. Circulation. 2000; 102:2726-2731.
- Blouin RA; Chandler MHH. Special pharmacokinetic considerations in the obese. Applied pharmacokinetics: principles of therapeutic drug monitoring. In: Evans WE, Schentag JJ, Jusko WJ, ed. Applied Therapeutics. 3rd ed. Vancouver, BC: Applied Therapeutics Inc; 1992:11.3-11.20.
- Westphal JF, Brogard JM. Clinical pharmacokinetics of newer antibacterial agents in liver disease. Clin Pharmacokinet. 1993; 24:46-58.
- Kirkwood CK, Melton ST. Anxiety disorders. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, ed. Pharmacotherapy: a Pathophysiologic Approach. 5th ed. New York, NY: McGraw Hill; 2002:1295.
- Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976; 16:31-41.
- Blouin RA, Bauer LA, Miller DD, Record KE, Griffen WO Jr. Vancomycin pharmacokinetics in normal and morbidly obese subjects. Antimicrob Agents Chemother. 1982; 21:575-580.
- Bauer LA, Black DJ, Lill JS. Vancomycin dosing in morbidly obese patients. Eur J Clin Pharmacol. 1998; 54:621-625.
- Heparin sodium for injection. Package insert. Deerfield, Ill: Baxter; 2004.
- Shepherd MF, Rosborough TK, Schwartz ML. Heparin thromboprophylaxis in gastric bypass surgery. Obes Surg. 2003; 13:249-253.
- Raschke R, Reilly B, Guidry JR, Fontana JR, Srinivas S. The weight-based heparin dosing nomogram compared with a standard care nomogram. Ann Intern Med. 1993; 119:874-881.
- Schwiesow SJ, Wessell AM, Steyer TE. Use of a modified dosing weight for heparin therapy in a morbidly obese patient. Ann Pharmacother. 2005; 39:753-756.
- Miller MT, Rovito PF. An approach to venous thromboembolism prophylaxis in laparascopic Roux-en-Y gastric bypass surgery. Obes Surg. 2004; 14:731-737.
Drs Lee, Winstead, and Cook are from UK HealthCare, Department of Pharmacy, University of Kentucky, Lexington, Ky.
Reprint requests: Aaron M. Cook, PharmD, 800 Rose St, Rm H-110, Lexington, KY 40536.