Pharmacy Purchasing & Products: What is the impact of the pharmacokinetic changes that occur with obesity?
Craig Martin, PharmD, MBA: The pharmacokinetic changes that occur in obese patients can present challenges when administering medications to this population. Various drug classes are affected differently by the condition, and as clinical studies describing the effects of medications on obese patients are sparse, the dearth of knowledge remains problematic.
Pharmacokinetic concepts are best understood by the ADME construct: absorption, distribution, metabolism, and excretion. The body composition changes that occur with obesity include an increased proportion of adipose tissue and decreased proportion of skeletal muscle. However, not all of the extra weight associated with obesity is adipose. Weight may be composed of both lean and fatty mass, with a higher proportion of fatty mass than lean mass. In addition to these body tissue changes, obese patients demonstrate a greater blood volume and glomerular filtration rate, which may affect drug concentrations. Further, the likelihood of renal damage due to diabetes or hypertension is elevated in obesity, so understanding the comorbidities present in each patient is crucial.1
The most prominent effect of these alterations is seen in the volume of distribution of the drug in question. Understanding how a drug is distributed in different body tissues is critical to predicting the effects of obesity on the drug’s serum concentrations. For example, a lipophilic drug, such as a macrolide antibiotic, will exhibit greater affinity for adipose tissue. In a patient with obesity, this may result in a much larger volume of distribution and lower serum concentration, when compared to a non-obese patient. Hydrophilic agents, such as beta-lactams, are likely to remain primarily in non-fatty tissues. Therefore, resulting concentrations may be closer to those in non-obese patients.
PP&P: What are the best methods for classifying the impact of obesity?
Martin: It is important to note that there are a variety of recommended methods for measuring and classifying obesity. Determining body composition and predicting its impact on the pharmacokinetics of a given drug has proven challenging, and a universally applicable approach remains elusive. For example, in some cases, it may be appropriate to use total body weight (TBW) when determining the best dose for certain drugs, but for other drugs, a risk of toxicity will present when dosing based on TBW.
Body Mass Index (BMI), promoted by the World Health Organization, is the most commonly used measurement for classifying individuals according to weight.2 This simple calculation is based on height and weight; for example, when comparing two patients of the same weight, the taller patient would have a lower BMI. Unfortunately, BMI is a notoriously inaccurate predictor of lean vs fatty body mass, especially at the extremes of body composition. Under the BMI measurement, 10 kg of muscle and 10 kg of fat are equivalent. A very lean, very muscular patient could be classified as obese when considering only that patient’s BMI. As adipose tissue and muscle tissue have different effects on drug distribution, BMI alone often proves too rudimentary to provide ample guidance in drug dosing.
Other metrics used with varying frequency include body surface area (BSA), lean body weight (LBW), ideal body weight (IBW), and adjusted body weight (AdjBW). The TABLE shows a comparison of methods used to classify the impact of obesity. AdjBW was developed specifically to aid in dosing certain medications. In effect, it accounts for the excess weight carried by overweight and obese patients, but includes consideration for the fact that not all of that excess weight is adipose tissue. Total body water is increased with obesity as well; taking this into account, the formula assigns 40% of the excess weight as water, allowing distribution of hydrophilic drugs, and 60% as adipose tissue.3 The most common use of AdjBW is in dosing aminoglycosides, a significantly hydrophilic group of antibiotics. AdjBW is calculated by multiplying the difference between TBW and IBW by 0.4, then adding it to IBW. The assumption is that aminoglycosides will distribute into 40% of the excess weight attributed to obesity. However, as with other measures, accuracy can vary. Aminoglycosides are usually monitored and adjusted by measuring serum concentrations, which is especially important in populations that may not be adequately studied, such as patients with obesity.
Clinically, the best approach to choosing the parameter on which to dose a medication combines investigation of the product labelling, the available literature, and the specific pharmacokinetic parameters of the drug. It is important to note that not all available medications have been investigated in obesity, so clinical judgment is often necessary.
PP&P: What drug classes are particularly impacted by obesity?
Martin: Almost any drug class can be affected by the physiologic changes that occur with obesity, but drugs with narrow therapeutic indexes (NTIs) require the most attention. Antibiotics, chemotherapeutic agents, analgesics, anticoagulants, and anticonvulsants are affected by volume and clearance anomalies; thus, it can be challenging to ensure therapeutic, safe concentrations for many drugs in these classes.
Vancomycin is typically dosed using TBW instead of AdjBW, owing to its enhanced lipophilicity over the aminoglycosides. However, most clinicians will choose to use the lower end of the recommended dosing range, especially in extremely obese patients. Institutions may implement a dosing cap, typically at 2 g per dose. While the currently available literature does not necessarily support this methodology, extremely obese patients are not often included in clinical trials, so a cautious approach is warranted.
For example, an investigation of the pharmacokinetics of cefazolin (2 g) in severely obese patients undergoing gastric bypass demonstrated a BMI-dependent likelihood of achieving adequate serum and tissue concentrations to kill target organisms. Patients with a BMI greater than 60 kg/m2 were 52% more likely to achieve adequate serum concentrations, but only 10% more likely to have necessary tissue concentrations at procedure closure. This study, combined with cefazolin’s favorable safety profile, demonstrates a need to use higher doses.5 Other investigations have demonstrated the safety of 3 g in obese patients.6
Opioid analgesics present a unique challenge, as identifying the appropriate balance between safety and efficacy is critical. In addition to the effects of obesity on drug concentration, it is important to consider the potential for drug tolerance in patients who may already be receiving opioids. A non-weight-based approach is recommended for dosing morphine; subsequent doses may be titrated based on response.9
Fentanyl is a highly lipophilic agent whose potency highlights the importance of cautious dosing. It is often dosed on a body weight basis in both obese and non-obese patients. Despite its strong lipophilicity, investigators have discovered a nonlinear association between average fentanyl dose needed and TBW. They warn of the risk of overdose in obese patients when TBW is used for calculating the dose. These researchers developed a weight correction, termed pharmacokinetic mass, to adjust for this nonlinearity (more information about weight correction is available at: https://bjanaesthesia.org/article/S0007-0912(17)36000-2/fulltext).10
PP&P: Are reimbursement issues a concern when dosing is tailored for a patient with obesity?
Martin: In the inpatient setting, medication reimbursement is typically included in bundled payments. Especially with expensive medications, higher doses used in obese patients can have a significant financial impact.
Each institution should evaluate ways to mitigate these effects; it is important to minimize waste, which can be achieved by dose standardization and batching. Although this approach is not appropriate for all medications, it may bring about favorable results in certain situations. For example, daptomycin doses may be rounded to the nearest vial size and administered at the same time for most patients. This increases the likelihood that, should the medication be discontinued after it is prepared, it may be used for another patient. Vancomycin administration can be handled in a similar fashion, with doses being rounded to the nearest 100 mg or 250 mg.
PP&P: What staff education should be provided regarding medication dosing for patients with obesity?
Martin: Medical, pharmacy, and nursing staff should receive education on the complexity of medication dosing in patients with obesity, as each department plays a unique role in the safe use of medications in this population. Pharmacists are best positioned to provide this education, which can be delivered in a variety of methods: in-service presentations, one-on-one consultations, e-prescribing alerts, newsletters, etc. The risk of medication errors can be higher in any unique patient group (such as pregnant women, pediatric patients, etc), and patients with obesity are no exception.
While pharmacists are clearly attuned to the potential danger of giving a patient an excessively high dose, in certain situations, the effects of underdosing can also be grave. For example, for patients with sepsis, adequate and timely antimicrobial administration improves mortality. Although the effect of underdosing in patients with obesity has not been examined, negative consequences are possible. Similarly, underdosing of anticoagulant medication may place the patient at higher risk of life-threatening clotting. Thus, it is appropriate to utilize an intentional, yet cautious approach wherein each health care provider takes extra care to understand the individual patient and the medications needed. There are no shortcuts, and the extra attention given could save lives.
PP&P: Looking to the future, what improvements should be made to ensure appropriate dosing for patients with obesity?
Martin: Additional research and astute examination are needed, with a particular focus on the impact of drug class and drug type on patients with obesity. To ensure patient safety, the pharmacokinetic changes that occur in obese patients must be understood in order to prevent over- or under-dosing, both of which could prove deadly.
Craig Martin, PharmD, MBA, is a professor in the department of pharmacy practice and science and the associate dean of the college of pharmacy at the University of Kentucky. He received his pharmacy degree from the University of Kentucky and his MBA from Morehead State University in Morehead, Kentucky. His professional interests include researching antibiotic use in hospitals and ambulatory settings, and developing novel teaching methods to educate the next generation of pharmacists.
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