Drug Dosing in Obesity

There is an obesity epidemic. Obesity is a worldwide problem with major health, social and economic implications. It has been caused by changes in diet and exercise as a result of increasing urbanisation and wealth in poorer nations. Changes to the diet have increased the availability of foods containing higher fat, higher salt, and higher carbohydrate levels, and is supplied to the consumer in larger portion sizes.

These issues have resulted in a population with an increasing percentage of overweight and obese people who may become patients in the medical system. Obesity itself causes an increased demand on the health system and a strong correlation has been shown between increased bodyweight and the prevalence of Type 2 Diabetes, heart disease, some types of cancer, and osteoarthritis.

How does Australia rate in these statistics?

Australia is now ranked as one of the top ten countries with the highest rates of obesity in the world.

Table 1. Percentage of overweight individuals in Australian States (Source: Australian Institute of Health and Welfare 2013).

The amount of lean body tissue does not stay the same as weight increases, but increases slightly, although not in a linear fashion in relation to total bodyweight. The increase in lean body weight (LBW) is shown in Table 2, as a percentage of the patient’s total body weight.

Table 2. Percentage of fat and lean body weight (% of total body weight).

People with obesity have a larger lean body mass and fat mass than non-obese persons matched on age, gender and height. However the percentage of fat per kilogram is markedly increased, while the percentage of lean tissue is reduced. Cardiac performance and adipose tissue blood flow may be altered and are usually reduced in obesity.

The adaption of drug treatment, particularly drug dosages for obese patients, is concerning and even more so with drugs that have a narrow therapeutic index. The factors which can affect the required drug dose are; the tissue distribution of drugs based on body composition, regional blood flow, and the affinity of the drug for plasma proteins and tissue components.

There is a growing literature base to suggest that the use of LBW, instead of ideal body weight (IBW), should be used to calculate drug doses to give a more accurate dose for overweight and obese patients. This is a sound suggestion, as 99% of the metabolic processes take place in lean body tissue.

It has also been postulated that there may be a relationship between LBW and hepatic functional capacity. Lean body mass is slightly different from fat-free mass because fat in cell membranes is included in LBW. Creatinine clearance can also be useful to assist in drug dosage calculations.

All patients admitted to hospital should be weighed as soon as possible after admission, to ensure this important information is available for consideration when determining drug doses.

What are the issues involved in calculating a drug dose?

• Clearance of drugs from the body is based on LBW;
• 99% of clearance occurs in lean tissue;
• Clearance is proportional to the LBW;
• Oral bioavailability is not affected;
• The effect on Vd (Volume of distribution) is related to the hydrophilic (water soluble) to lipophilic (fat soluble) ratio (e.g. for Phenytoin);
• Whether the dose should be capped to provide a maximum dose;
• What is the most accurate way to calculate the dose; and
• Which drugs are the most difficult to calculate.

There are many drugs with doses that are of concern for overweight patients, such as;

• Those with a narrow therapeutic index, such as gentamicin and vancomycin. Monitoring of the blood levels of these drugs to ensure that therapeutic level is rapidly achieved without
  adverse effects.
• Australian Medicines Handbook (AMH) recommends if a patient is >20% overweight, usually IBW is used to calculate the dose. Renal function must also be considered.
• An adjusted gentamicin dose can be calculated by: Adjusted weight = 0.4 x (actual weight – ideal weight) + ideal weight
• Individualised dosing should be based on concentration monitoring, for example therapeutic drug monitoring with a Targeted Concentration program such as TCI Works^®.

Many hospitals provide guidelines for gentamicin and vancomycin with dose adjustments based on IBW or LBW.

Enoxaparin could be considered one of the most difficult drugs to dose accurately for an obese patient. Opinions differ widely about the most appropriate dose for overweight and obese patients. Many clinicians increase doses to a predetermined maximum dose up to a body weight of 100 or 120kg, for example:

• There is research into the use of a graduated dose regimen with 1mg/kg twice a day if TBW<100kg and 1.5mg/kg if TBW>100kg.
• Trough Factor Xa levels can be useful to monitor therapeutic levels.
• Renal impairment should always be checked before doses are prescribed or given. The AMH recommends dose reduction in renal impairment if CrCl<30ml/min for enoxaparin.
• Gentamicin and vancomycin doses are also adjusted for renal function and will require extra monitoring if renal impairment is present.

Drug dosing in the overweight and obese patient remains a much debated issue with few clear guidelines available. Research is increasing in this area to give more clarity.

The increasing rate of obesity in Australia should be addressed urgently as a community to reduce the rates of overweight and obese people and improve the health of future generations.