The illusion of a single perfect dose

Imagine if the recommended dose of a medication, the dose printed on its package, was correct for only about half of the people taking it. Then picture some people needing 30 times as much of the drug as others. What if either too high or too low a dose could have life-threatening consequences?

This worrisome scenario is the reality for patients taking warfarin, the 59-year-old blood thinner meant to help people avoid blood clots.

It serves as an example of the fact that, for many drugs, the idea of one correct dose for everyone is an illusion. In this light, I find it strange to think that the doses of medications I took growing up were best guesses, based on things like body weight, age, sex and race.

A wave of studies in recent years revealed that each person's genetic quirks greatly influence how well his or her body uses a drug, and on top of the classic factors mentioned above. How each person processes a drug determines not only whether or not that drug will work for them at all, but also how much of it is needed. Human genetic material is always changing, and many small variations at key spots in genes across a population create a range of responses to the same drug. Complicating matters, some of the variations with an impact on drug response are different for people with different ancestries.

That brings us to a study published this week and co-led by a UAB researcher. It found that a new genetic marker can better predict the right starting dose of warfarin dose in African-Americans. If confirmed in further studies, the finding may help avert more of the bleeds and blood clots that come when a patient’s  dose misses the drug’s narrow safety window.

Clots form to patch holes in blood vessels. Unfortunately, clotting can also be triggered by atrial fibrillation, cancer, surgery, aging and inactivity. Once formed, clots can float through the circulatory system to clog blood vessels elsewhere, causing heart attacks and strokes.

For these reasons, 33 million Americans got a prescription for warfarin in 2012, most of whom started on an average starting dose of 5 mg. The drug is very effective at preventing clots, but if the dose is too-high for any individual, that patient is at risk for internal bleeding. If the dose is too small, they may not be protected against clots. Doctors monitor patients' clotting speed closely in the first few weeks of treatment, trying to get each person's dose right before serious side effects occur. Such efforts fail often enough that warfarin made a recent top-ten list of drugs causing side-effect related hospitalizations in the United States, mostly because of bleeds.

Most of why dose varies so greatly across the population remained unexplained. A study just published in The Lancet and co-led by UAB's Nita Limdi, Pharm.D., associate professor in the Department of Neurology within the UAB School of Medicine, chipped away at this mystery.

The new study was a genome-wide association (GWA) study, a kind of analysis that looks at differences in genetic code to see if one or more variations are found more often across a population with a given trait. Traits can be high risk for a disease, needed drug dose or how tall you are. Even the smallest genetic variations, called single nucleotide polymorphisms (SNPS), can have a major impact on a trait by swapping just one of 3.2 billion “letters” making up the human DNA code.

The current GWA study found a statistically significant association between a SNP called rs12777823 and reduced warfarin dose requirements in African-Americans. Patients with this SNP needed 20 percent less warfarin, an effect not seen in patients of European or Asian ancestry. When incorporated into dosing algorithms, the new variant enabled the prediction of best dose with 21 percent greater accuracy than the standard formula. Past GWA studies had sought to identify genetic factors that could improve warfarin dose prediction, but none of them included patients of African ancestry.

For more information, see our press release on the study.