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.

• Low Molecular Weight Heparin. The impact of obesity on low molecular weight heparin agents, such as enoxaparin, lacks clarity at the present time. The FDA-approved dose of enoxaparin for the treatment of venous thromboembolism (VTE) is 1 mg/kg every 12 hours. Standard practice has been to use TBW for this dosing, but more recent studies that have used a target anti-Xa level suggest lower dosing strategies may be warranted.4 Significant controversy exists regarding the decision to implement a dose cap in morbidly obese patients. In the era of anti-Xa monitoring, clinicians are able to provide a more tailored dosing regimen for each patient.

• Warfarin. With regard to the NTI exhibited by warfarin, dosing is highly variable and can be adjusted based on the International Normalized Ratio (INR). While obese patients may require higher doses, the use of INR monitoring can provide a measure of confidence that the drug is being used safely and effectively.

• Vancomycin. Vancomycin and aminoglycosides are often monitored by serum concentration. The challenge lies in the need to accurately estimate patient-specific pharmacokinetic parameters, such as volume of distribution and clearance when determining initial doses. As mentioned earlier, aminoglycosides are usually dosed based on AdjBW. Although capping the dose is typically not considered, extremes of obesity have not been well studied. In such cases, it is imperative to monitor and react to serum concentrations in a timely fashion. Delayed response can result in sub- or supra-therapeutic (ie, toxic) drug dosing. When concentrations are measured, the need to estimate parameters is eliminated; the patient-specific volume of distribution and clearance can simply be calculated.

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.

• Cefazolin. Cefazolin treats a variety of infections, and is perhaps most commonly used for perioperative prophylaxis in certain high-risk operative procedures. Historically, a single-gram dose prior to incision, with the possibility of a second dose for procedures lasting longer than 4 hours, was used. Early recommendations failed to recognize the importance of body weight as a significant factor in preoperative dose selection, but recent studies have demonstrated a need to increase doses in some patients.

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

• Daptomycin. The FDA-approved approach to dosing daptomycin is weight-based. As with nearly all drugs, the impact of obesity on its pharmacokinetics was unknown at the time of FDA approval. Since then, investigators have sought to determine the best method of dosing in obese patients. Soon after drug approval, investigators measured serum concentrations in obese patients and compared them to non-obese patients. While obese patients who received the same mg/kg dose had greater drug exposure, it was noted that concentrations remained in the range considered safe.7 Indeed, daptomycin is a concentration-dependent killer of bacteria, so enhanced serum concentrations may augment its bactericidal activity. Recent research compared outcomes when doses were based on AdjBW or TBW in a retrospective analysis. Although the study had a small sample size and was retrospective in nature, it should be noted that no differences were found in clinical efficacy.8

• Analgesics. Obesity-related differences vary widely among analgesics. Acetaminophen is not broadly distributed into adipose tissue, so the non-weight-based dosing approach used in non-obese adults applies for obese patients. Ibuprofen concentrations have been demonstrated to be lower in obese patients, and some clinicians recommend a dose adjustment based on the level of obesity. Toxic effects on the kidneys must be considered, however, so clinicians are urged to proceed with caution.

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

• Chemotherapy. Historically, chemotherapeutic agents have been among the most toxic compounds used in clinical medicine. In addition, the correlation of obesity with many cancers enhances the likelihood that obese patients will need to receive these agents. Most current chemotherapy protocols utilize BSA to determine the proper dose. Out of a desire for caution, BSA is often capped for patients with severe obesity. This complicates therapy, as the proper approach to dosing of most agents has not been well studied for extremes of weight. It is possible that some protocols underdose the drugs in these situations, increasing the opportunity for treatment failure.

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.

References

1. Zuckerman M, Greller H, Babu K. A review of the toxicologic implications of obesity. J Med Toxicol. 2015;11(3):342–354.
2. World Health Organization. Global Health Observatory (GHO) data. Mean Body Mass Index (BMI). www.who.int/gho/ncd/risk_factors/bmi_text/en/. Accessed May 3, 2019.
3. Bauer LA, Blouin RA, Griffin WO Jr, et al. Amikacin pharmacokinetics in morbidly obese patients. Am J Hosp Pharm. 1980;37(4):519-522.
4. Lee YR, Vega JA, Duong HN, et al. Monitoring enoxaparin with Antifactor Xa levels in obese patients. Pharmacotherapy. 2015;35(11):1007-1015.
5. Edmiston CE, Krepel C, Kelly H, et al. Perioperative antibiotic prophylaxis in the gastric bypass patient: do we achieve therapeutic levels? Surgery. 2004;136(4):738-747.
6. Young OM, Shalk IH, Twedt R, et al. Pharmacokinetics of cefazolin prophylaxis in obese gravidae at time of cesarean delivery. Am J Obstet Gynecol. 2015;213(4):541.e1-7.
7. Dvorchik BH, Damphousse D. The pharmacokinetics of daptomycin in moderately obese, morbidly obese, and matched nonobese subjects. J Clin Pharmacol. 2005;45(1):48-56.
8. Fox AN, Smith WJ, Kupiec KE, et al. Daptomycin dosing in obese patients: analysis of the use of adjusted body weight versus actual body weight. Ther Adv Infect Dis. 2019;6:2049936118820230.
9. Patanwala AE, Holmes KL, Erstad BL. Analgesic response to morphine in obese and morbidly obese patients in the emergency department. Emerg Med J. 2014;31(2):139-142.
10. Shibutani K, Inchiosa MA Jr, Sawada K, et al. Pharmacokinetic mass of fentanyl for postoperative analgesia in lean and obese patients. Br J Anaesth. 2005;95(3):377-383.

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.