Different medication dosage for morbidly obese patients

PhD research recently completed by pharmacologist Margreke Brill shows that morbidly obese patients should be given a different dosage of the drugs Cefazolin and Midazolam. This could also apply to other drugs such as anti-cancer drugs as well as antibiotics and Margreke Brill is advocating a change in the dosage guidelines. PhD defence 3 December at the Leiden Academic Centre for Drug Research (LACDR).

More Midazolam and Cefazoline

A person with a BMI of 40 who is 1.75 m tall weighs 125 kilos.

A person with a BMI of 40 who is 1.75 m tall weighs 125 kilos.

There are indications that medication works differently in people suffering from morbid obesity, or in other words, individuals with a body mass index (BMI) over 40. However, the exact mechanisms behind this phenomenon are largely unknown. ‘Because of this, we do not know whether we need to adjust the dosage of many drugs for obese patients,’ says Margreke Brill of St. Antonius Hospital Nieuwegein/Utrecht. In a clinical study, she investigated the blood and tissue concentrations of the sedative and anaesthetic Midazolam as well as the antibiotic Cefazolin in this group of patients. She discovered that lower levels were recorded in obese patients. Given this finding, she recommends adjusting dosages for such patients.

Medication is distributed throughout fat tissue

‘So far, the medical understanding has been that, in morbidly obese patients, the liver metabolises the sedative and anaesthetic Midazolam less rapidly,’ says Brill. ‘My research shows that to be inaccurate: the rate of drug metabolism appears to be the same for obese patients.’ However, the pharmacologist stumbled upon another difference: Midazolam is distributed heavily throughout fat tissue. ‘Doctors should therefore provide more Midazolam in specific cases than they currently do, in order to achieve the desired blood concentrations.’

Preventing wound infections

The dosage for the antibiotic Cefazolin should also be increased in obese patients. This drug is used in surgery to prevent wound infections. It is well known that morbidly obese individuals are more likely to suffer wound infections after an operation. Brill discovered that Cefazolin is distributed less effectively in the skin at the site of the surgical incision compared to non-obese patients and thus, has a lower impact. This is probably due to slower circulation or a larger body mass, throughout which the medicine must be distributed. To counteract this, a higher dosage needs to be administered to achieve the same concentrations in the skin, Brill states.

Increased dosage of anti-cancer drugs and antibiotics as well

The recommendation to increase the dosage may apply not only to Midazolam and Cefazolin. ‘Like Midazolam, many drugs are broken down with the CYP3A enzyme,’ says Brill. ‘These include some statins, anti-cancer drugs and antibiotics. Additional research is needed to confirm this, but it is suspected that these drugs should also be dosed differently in patients with morbid obesity.’

Taking medical history into account

Brill advises doctors to also look at patients’ medical history. ‘You cannot compare one eighty-kilo person with another. Someone who has undergone gastric reduction surgery may also respond differently to medication.’ Brill discovered that after such an operation the metabolism of Midazolam increases in the body. ‘This is probably because the effect of the CYP3A enzyme in the liver increases after gastric reduction surgery, given that the liver is recovering from possible fatty degeneration.’ This discovery could be used to work out dosage recommendations in patients after gastric reduction operations.

PhD defence Margreke Brill

(1 December 2015)

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Science dossier Effective Drug Development

Last Modified: 02-12-2015