The Daniel K. Inouye College of Pharmacy Scripts

The increasing prevalence of obesity has led to a global epidemic and a growing public health concern since obesity is a known risk factor for increased healthcare related morbidity and mortality.^1,2 Hawai‘i's obesity rate of 22.7% ranks as the 3rd lowest obesity rate in the United States, and its territories.³ However, Native Hawaiians or Pacific Islanders (NHOPIs) make up 26% of Hawai‘i's population and prevalence of obesity in this population is approximately 55%.^4,5 Although Hawai‘i was rated as the healthiest state in the nation for 2016, local clinicians still face the issues of treating obese patients and their associated comorbidities of diabetes, cardiovascular disease, stroke, and cancer.^2,6

One of the burning questions encountered for many clinicians when treating the obese population is, “Does this drug dose fit my patient?”

The World Health Organization (WHO) classifies obesity based on body mass index (BMI), a parameter calculated as a person's weight in kilograms divided by their height in meters squared. Generally, obesity is defined as having a BMI greater than 30 kg/m². The WHO further breaks down obesity into the following classes; class I, II, and III defined as a BMI of 30 to 34.9 kg/m², 35 to 39.9 kg/m², and greater than or equal to 40 kg/m², respectively.⁷

Drugs are commonly dosed using the FDA approved “one size fits all” dose, but some medications can be dosed by patient's weight, ie, mg/kg. Nevertheless, these dosing recommendations are largely based on studies that excluded obese patients, and do not take into account the pathophysiologic changes that may alter the effects of drugs in patients with obesity.^8,9 The concept of a “one size fits all” dose remains a topic of debate with respect to safety and efficacy of pharmacologic treatments. Common drug classes that continue to have the “Obesity Drug Dose Debate” are anticoagulants and antimicrobials.

Pharmacokinetics and Pharmacodynamics

Pharmacokinetics (PK) is described as the physiological effects of the body on a drug's absorption, distribution, metabolism, and elimination. Pharmacodynamics (PD) is described as the physiological effects of the drug on the body and may be thought of in terms of efficacy and toxicity.¹⁰ The relationship between PK and PD can be seen in Figure 1.

Figure 1.

The relationship between pharmacokinetics and pharmacodynamics with respect to the effects of drug dose on the body.⁴³

The highly varying physiology of patients with obesity may yield differing PK parameters such as volume of distribution (Vd) and drug clearance (Cl), than those seen in population clinical studies. Vd refers to the size of a body's compartment that needs to be “filled” in order to maintain the same concentration in the plasma. Changes in Vd would primarily alter the PK profile of lipophilic drugs, although hydrophilic drugs could also be affected due to an increase in the volume of lean muscle mass.¹¹ Alterations in Vd and drug plasma concentrations may occur due to the increased ratio and distribution of fatty tissue to lean body mass. An increase in fatty tissue will increase the Vd for drugs with high lipophilicity, the ability of a chemical compound to dissolve in fats. This increase in drug sequestration in fatty tissue, then can theoretically decrease the drug plasma concentration, resulting in a failure of a given dosage of drug to achieve the desired response.

Drug clearance (Cl) is the ability of the body to remove drug from the blood or plasma.¹⁰ Hydrophilic drugs are mainly eliminated through the kidney.¹² In obese patients, renal clearance may be increased, possibly through “obesity-related glomerulopathy,” which is associated with increased renal plasma flow and increased filtration rate; however, this is not observed as a linear correlation with total body weight and calculation of Cl in obese is not well validated. ^{11, 13, 14} These changes in PK ultimately affect PD in obese patients, which leads to potentially enhanced, diminished, or delayed drug effects.

Furthermore, confounding variables occur during acute illness, such as decreased hepatic blood flow and acute kidney injury, may also alter Vd and Cl, further complicating drug dosing in obese patients. If higher doses are given in obese patients to accommodate for higher weight, there is concern for supratherapeutic responses and if doses are capped based on max doses for non-obese patients, there is concern for subtherapeutic responses to the administered drug. The conundrum of under versus over dosing in obese patients may lead to suboptimal treatment or increased adverse drug effects, respectively, both with potentially detrimental outcomes. Understanding the basic drug PK and PD variations that occur in obese patients allows for personalized care and may lead to improved clinical outcomes.

This paper addresses the issue of drug dosing in obese patients, specifically with anticoagulants and antibiotics. Proper dosing is necessary to assure optimal safety, efficacy, and additionally in the case of antibiotics, minimize the development of bacterial resistance.

Anticoagulants

Currently, there is a lack of standardized protocols and guidance on how to optimally dose both oral and injectable anticoagulants for therapeutic anticoagulation in obese patients. Controversy remains on whether these patients should be dosed by a fixed dose or dosed by weight for the most effective therapeutic interventions. Recommended fixed doses may be sub-therapeutic and thus raise the concern for an increased risk for clot formation. On the other hand, dosing by total body weight in obese patients raises concerns for over-anticoagulation and the increased risk of bleeding.

Enoxaparin

Enoxaparin is an injectable anticoagulant commonly used for venous thromboembolism (VTE) treatment and prophylaxis. Obesity itself is considered a risk factor for VTE, and the dose for pharmacological treatment and prophylaxis in patients with obesity remains patient specific and varies between clinicians.^15,16 Enoxaparin doses of 40 mg daily for VTE chemoprophylaxis and enoxaparin 1 mg/kg twice daily for VTE treatment are recommended by different studies and are commonly used in practice. Although there is a lack of consensus regarding the optimal size descriptor (lean versus total body weight in varying BMI) for determining weight-based doses in patients with obesity, studies have shown that weight-based dosing has benefit for patients who fall into the category of Class 3 obesity (≥40kg/m²) and those who are above 190kg.^11,17,18

A 2010 study by Freeman and colleagues compared the standard enoxaparin 40 mg daily fixed dose for VTE prophylaxis to high-dose (enoxaparin 0.5 mg/kg daily) and low-dose (enoxaparin 0.4 mg/kg daily) weight-based dosing in morbidly obese patients. ¹⁵ The outcomes of the Freeman study showed that the high-dose, weight-based dosing group achieved target anti-Xa levels (0.2–0.5 IU/mL) more frequently, showing favor for the non-fixed, weight-based dosing.¹⁵ In a 2011 case series by Deal and colleagues, enoxaparin doses for treatment of VTE correlated to anti-Xa levels in the morbidly obese. It was found that weight-based dosing of 1 mg/kg every 12 hours, with a maximum dose of 150 mg every 12 hours, resulted in enoxaparin doses ranging from 0.67 mg/kg to 1 mg/kg (median 0.8 mg/kg) with steady state anti-Xa levels falling within or above goal with no levels below goal.¹⁹ While this case series favored capping the dose of enoxaparin for VTE treatment in morbidly obese patients in order to reduce risk of bleeding, other studies for VTE prophylaxis have determined that not capping doses for obese patients allows for appropriate achievement of therapeutic anti-Xa levels without increasing the risk of bleeding.^19–21 Thus, enoxaparin dosing in obesity remains highly controversial due to the lack of qualitative studies and the varying pharmacokinetic and pharmacodynamic alterations in the obese population altering Vd and Cl.²²

Anti-Xa levels are commonly used in clinical practice to determine the degree of anticoagulation from enoxaparin. It is recommended to use these levels for monitoring enoxaparin dosing in obese patients to determine the safety and efficacy of the drug.²³ Established anti-Xa levels commonly used in practice are 0.5 to 2.0 IU/mL for full therapeutic dosing and 0.18 and 0.44 IU/ml for prophylactic dosing.²⁴ However, due to variations in individual institutional assays, it may be best for individual institutions to develop their own ranges.

Oral Anticoagulants

Direct oral anticoagulants (DOACs) target a specific factor in the clotting cascade, whereas warfarin, the hallmark anticoagulant, targets multiple clotting factors. DOACs such as dabigatran, rivaroxaban, apixaban, and edoxaban, are becoming more commonly used for treatment of venous thromboembolism (VTE) and for stroke prevention in atrial fibrillation due to their ease of use and relatively favorable safety profiles compared to warfarin. Many of the landmark trials, which led to the Food and Drug Administration (FDA) approval of these drugs, did not include patients with morbid obesity (>120 kg or BMI >40kg/m²). In the six years since the FDA approved these DOACs, sparse post-marketing PK and PD data has not helped prescribers to appropriately dose these agents in obese patients. Early PK studies of rivaroxaban and apixaban in healthy subjects, showed little difference in the peak or trough levels after one dose of each drug in subjects with normal weight versus those with weight >120kg.^25,26 Yet, in a recent review of DOACs by Buckley and colleagues, apixaban and rivaroxaban were reported to have reduced levels in obese patients, although the effect of this was not demonstrated in the clinical outcomes. Because of a lack of PK, PD, and clinical outcomes data for dabigatran and edoxaban, these drugs are typically not included in the ongoing debate on dosing in obese patients.²⁷

Unlike enoxaparin, laboratory tests that can determine the degree of anticoagulation with DOAC's are not currently available for use in clinical settings. With little post-hoc analysis and clinical laboratory tests available to better inform clinicians on the degree of anticoagulation, caution should be exercised in dosage adjustments when using DOACs in obese patients.^27,28

Antibiotics

Obesity has been regarded as a risk factor for infectious disease, and has been associated with poorer outcomes for many infectious disease states including bacteremia, nosocomial infections, surgical site infections, and skin infections.^29,30 The PK changes in obese patients affect antibiotic therapy, and should be taken into consideration for optimal antibiotic treatment in this population at risk for infectious complications. Three important antibiotic PD concepts include: (1) time of exposure of bacteria to an antibiotic, T>MIC; (2) the maximum achieved concentration of antibiotic in the body (Cmax/MIC); and (3) the combination of time and concentration (AUC/MIC).³¹ The concept of time of exposure describes the time that a certain drug concentration is over the minimum inhibitory concentration (MIC), which is commonly referred to as T>MIC. A minimum inhibitory concentration (MIC) is the minimum concentration of antibiotic needed to inhibit visible growth of bacteria in a test tube. The more time (T) the concentration of the antibiotic in the body is above the MIC, the higher the bacterial kill. The second concept focuses on concentration of antibiotic in the body. Cmax is the highest concentration of the antibiotic achieved in the body after a dose is administered. The higher the ratio of Cmax/MIC (high Cmax/low MIC) the more effectively the antibiotic is able to kill the bacteria. The last concept is a combination of time dependent and concentration dependent killing that looks at the total exposure of the drug in the body or area under the curve (AUC). A larger AUC over a low MIC in a 24-hour period of time is another indication of antibiotic effectiveness in killing bacteria. The optimal ratio of AUC/MIC depends on the type of bacteria and specific antibiotic used, where the largest effect is seen when antibiotic exposure is maximized with respect to the MIC. ³¹

Alterations in PK and PD parameters in patients with obesity, affect drug concentrations in the body and may directly affect the three concepts just reviewed. With the exception of a few antibiotics (aminoglycosides, vancomycin, daptomycin), there remains a paucity of data in regards to dosing antibiotics in the obese population. ³² Based upon dosing guidelines, the following recommendations outline the dosing of aminoglycosides, beta-lactams and vancomycin in obese patients.

Aminoglycosides

Aminoglycosides, such as gentamicin, amikacin and tobramycin, are hydrophilic molecules that rely on concentration dependent killing for efficacy. For non-obese patients, ideal body weight is typically utilized for dosing.³³ For the obese population, this approach might result in subtherapeutic serum concentrations, and thus, several studies suggest using dosing based on an adjusted body weight (ABW), with a correction factor of 0.4 for the additional weight in kilograms over the IBW. Prior studies, using ABW have demonstrated an improved prediction of aminoglycosides' Vd and is considered the best approach to tackle the increased total body clearance.³¹ Therapeutic drug monitoring of aminoglycosides is recommended with drawing of appropriately timed peak and trough levels.

Beta-lactams

Beta-lactams are widely utilized and are comprised of penicillins, cephalosporins, carbapenems, and aztreonam. These hydrophilic molecules rely on time dependent properties of antibiotics for efficacy. Very few studies have evaluated dosing of penicillins in patients with obesity but some suggest using the upper end of the dosage ranges.³² A study evaluating standard doses of piperacillin-tazobactam in patients with complicated intra-abdominal infections, found lower cure rates in patients with a BMI of 30 kg/m² or more.³⁴ PK/PD studies suggest using an extended infusion time of 4 hours (rather than the standard 30 mins) for piperacillin-tazobactam to achieve optimal levels for good outcomes. The extended infusion model was further validated in a case-study of a morbidly obese patient in whom piperacillin-tazobactam infused at a higher dose and extended time more consistently achieved desired levels and cure rates than the standard dose and infusion time.³⁵ Cefazolin is widely utilized for prevention of surgical site infections. Obese patients receiving a higher dose of 2 g versus the standard 1 g dose had lower rates of perioperative wound infections.³⁶ Similarly, a higher dose of cefepime (2 g every 8 hours) was needed in morbidly obese patients to achieve appropriate T>MIC of at least 60%.³⁷ There are conflicting studies for the dosing of ertapenem. One study showed that lower concentrations of the antibiotic are achieved in obese patients who received the usual 1 g dose, resulting in inadequate treatment for patients with bacteria that exhibited higher MICs.³⁸ Another study demonstrated identical cure rates in both patients with BMI of less than 30 kg/m² and more than 30 kg/m² when ertapenem was used for complicated intraabdominal infections.³⁴ Lastly, a study that examined aztreonam in obese patients had a much lower AUC, potentially due to higher Vd and Cl, and did not achieve therapeutic levels of aztreonam in obese compared to non-obese patients.³⁹

Vancomycin

Vancomycin is another hydrophilic molecule that depends on AUC/MIC ratio for efficacy. In the treatment of Methicillin-Resistant Staphylococcus Aureus (MRSA), a resistant bacteria for which vancomycin is the drug of choice, an AUC/MIC ratio of at least 400 is needed to achieve optimal outcomes. Several studies concluded that actual body weight should be used for dosing vancomycin in obese patients, rather than using a standardized defined dose, in order to achieve therapeutic vancomycin levels and optimal AUC/MIC ratios of >400.⁴⁰ This is because vancomycin clearance in obese patients is higher than other patients, likely due to obesity related glomerulopathy, thus necessitating higher doses. Total body weight seems to be adopted by many institutions for determining loading doses of vancomycin with a cap of 2 or 3 grams.⁴¹ However, the higher dosing may cause adverse effects: one study found a higher instance of nephrotoxicity in patients above 100 kg.⁴¹ Maintenance dosing, however, seems to be more related to the measure of renal function rather than weight.⁴²

Conclusion

This review discusses the variations in PK and PD parameters in patients with obesity and reviews some of the different dosing strategies for commonly used anticoagulants and antibiotics. The movement towards “patient specific” care should be taken into consideration for drug dosing in obese patients. PK and PD alterations as well as physiological changes during acute illness require close monitoring to determine the safety and efficacy of these commonly used drugs in obese patients. More studies are needed that incorporate larger population samples with BMI > 40kg/m² to better understand and personalize pharmacotherapy for obese patients.