Predicting drug dosing in obese patients can be a challenge

March 2008

Consider the following scenario: you are examining a 7-year-old boy in your office for otalgia. You diagnose bilateral acute otitis media and decide to prescribe amoxicillin liquid, as the child cannot swallow tablets.

This 7-year-old weighs 190 lb. Using a dose of 45 mg/kg/day, you calculate a dose based on the child’s weight, 1,944 mg twice daily (3888 mg/day). Using the 400 mg/5 mL product, this equates to a volume dose of 24 mL twice daily. Alternatively, using 400 mg chewable tablets, the dose is five chewable tablets twice daily. The usual adult dose of amoxicillin is 500 to 875 mg twice daily, with a maximum daily dose of 2,000 to 3,000 mg. What dose should be prescribed?

A reader of Infectious Diseases in Children recently raised this clinical scenario. With the increasing prevalence of overweight and obesity in children, similar scenarios may be common. A review of the published literature reveals some studies addressing drug dosing in obesity. Unfortunately, most of these studies have been conducted in adults.

Obesity causes numerous physiologic changes that may affect the pharmacokinetics and pharmacodynamics of drug therapy. Obesity results in not only an increase in adipose tissue mass, but also an increase in lean tissue mass (up to a 20% to 55% increase). Other changes include increased organ mass, cardiac output, and blood volume. Drug binding to alpha-1 acid glycoprotein may be altered. Drug binding to albumin does not appear to be significantly altered. Evaluating these physiologic changes and predicting the effects upon drug distribution, metabolism, and excretion are very difficult.

An important drug characteristic to consider is lipophilicity. Generally, highly lipophilic drugs distribute well into adipose tissue. This will affect the drug’s volume of distribution, likely increasing it. A larger volume of distribution may necessitate the use of a larger dose. Examples include the benzodiazepines, such as midazolam or diazepam, which are highly lipophilic compounds. Diazepam’s volume of distribution may increase 10-fold in obese individuals due to its increased volume of distribution. Verapamil and lidocaine also have greatly increased volumes of distribution in obese individuals. Digoxin and cyclosporine, however, two lipophilic drugs with relatively high volumes of distribution, do not appear to distribute significantly more in obese patients. Thus, predicting drug behavior in obesity is difficult, and is best characterized by adequate pharmacokinetic and clinical studies.

Many antibiotics are hydrophilic compounds, distributing mainly to extracelluar water, and thus they do not distribute extensively into adipose tissue. As adipose tissue contains approximately 30% water content relative to other tissue, many antibiotics will not distribute extensively more in obese individuals. Correction factors may be used to adjust drug dosing for hydrophilic drugs. For example, a correction factor of 0.4 has been recommended for aminoglycoside dosing in obese children. Correction factors (CR) are used by the following equation: Drug dose = CR (actual body weight – ideal body weight) + ideal body weight. Ideal body weight can be determined by using the child’s proportional percentile weight from height-weight growth charts. Alternatively, lean body mass (kg) may be determined by the formula: (height in cm) 2 x 1.65/1000. Correction factors for the following drugs have been recommended: beta-lactams – 0.3; ciprofloxacin – 0.45. The correction factor for beta-lactam drugs is an estimate, and is not based upon clinical studies. Recommendations for dosing of other antimicrobials include use of actual body weight for vancomycin and ideal body weight for macrolides and acyclovir. When possible, it is important to use plasma drug level monitoring (eg, aminoglycosides, vancomycin) to guide drug dosing, as drug disposition can vary widely in obese individuals, and because drug dosing in obesity has not been well studied in children.

Hepatic metabolism and renal excretion may also be affected by obesity. Some studies indicate that hepatic phase-2 metabolism reactions are increased in obesity. Acetaminophen is hepatically metabolized primarily by glucuronidation and sulfation, and there is some evidence in obese adults of increased clearance of acetaminophen. How this translates to acetaminophen dosing in overweight children is not clear. Some studies have indicated that obese individuals may also have increased glomerular filtration and creatinine clearance, resulting in increased clearance of some renally eliminated drugs, such as aminoglycosides and vancomycin. There is some evidence that nephrotoxicity of aminoglycosides is enhanced in obese adults. These potential changes in drug disposition in obese individuals highlight the need for increased vigilance of drug efficacy and safety, and the use of plasma drug level monitoring when possible.

Conclusion

The effects of obesity on drug behavior and clinical efficacy and safety are unknown for many drugs. Most of the available information evaluating drug changes in obese individuals comes from the adult literature. How these changes relate to the pediatric population is largely unknown.

The pharmacokinetic disposition of some drugs may best correlate with lean body mass, total body weight, or somewhere in between. It may be best to be conservative when dosing drugs in overweight children, especially when using drugs with a narrow therapeutic index. Plasma level monitoring should be employed when therapeutic levels are known for a drug.

In response to the clinical scenario discussed above and raised by a reader, assume the child plots at the 50% for height-for-age. The child’s lean body mass would be 52 lb (23.6 kg). Using a correction factor of 0.3 for amoxicillin, a dose of 980 mg twice a day would be determined. Other considerations include the severity of the child’s infection and the therapeutic index of amoxicillin. As the correction factor used is empiric and not based upon pediatric pharmacokinetic studies, a dose of 550 to 980 mg twice a day may be used for this child. A dose based upon actual body weight would not be appropriate.

For more information:

• Edward Bell, PharmD, is a Professor of Pharmacy Practice at Drake University College of Pharmacy at Blank Children’s Hospital in Des Moines, Iowa.
• Blouin RA. Pharmacokinetic considerations in obesity. J Pharmaceut Sciences. 1999;88:1-7.
• Wurtz R. Antimicrobial dosing in obese patients. Clin Infect Dis. 1997;25:112-8.
• Cheymol G. Effects of obesity on pharmacokinetics, implications for drug therapy. Clin Pharmacokinetics. 2000;39:215-31.
• Pai MP. Antimicrobial dosing considerations in obese adult patients. Pharmacotherapy. 2007;27:1081-91.
• Dudlye MN. Antibiotic dosing in obese children. Pediatric Infect Dis J. 1993;12:420