Different patients, different doses

The growing trend toward personalized medicine may offer opportunities for physicians to better tailor the dosages of some of their most commonly recommended or prescribed medications.

For example, as many as 25% of primary care patients may be taking a medication that causes an adverse drug reaction because of genetic variability in how that drug is metabolized, according to a 2006 study published in Pharmacogenetics.

“The majority of people metabolize drugs the same way—their bodies are very similar—but a handful of people metabolize certain drugs differently,” said Barton Cobert, MD, FACP, a drug safety expert and consultant in Chapel Hill, N.C. “Primary care physicians tend to prescribe the same 30 to 40 medications 90% of the time, so it is important for them to know any safety or dosing issues for those most commonly used drugs.”

One of the most well-known examples is warfarin. Genetic differences in two genes that the drug targets, VKORC1 and CYP2C9, account for some of the variability in patient response and also allow physicians to monitor the drug's effect and tailor dosing. A 2010 study published in the Journal of the American College of Cardiology showed that genotyping reduced the risk of hospitalization in patients starting warfarin by about one-third.

In addition, research published in 2004 in Clinical Pharmacology & Therapeutics identified a link between ibuprofen clearance and CYP2C8 and CYP2C9 polymorphisms. In the small study, almost one in five patients with the common genotype CYP2C8*1/*3 plus CYP2C9*1/82 had significantly decreased ibuprofen clearance compared with individuals without these mutations.

More recently, in 2018, Stefan Zajic, PhD, and colleagues published a study in Pharmacogenetics and Genomics showing that patients with these same genetic variations often recognize that they get sufficient efficacy from ibuprofen at a lower dose. Although a large trial would be needed to quantify any increased adverse effects among people with reduced ibuprofen clearance, they are likely experiencing higher concentrations, reflected by their ability to accurately judge when to take lower doses, explained Dr. Zajic, who is a principal research scientist at Coriell Institute for Medical Research in Camden, N.J.

“In terms of over-the-counter drugs, another class with a good deal of evidence for the impact of genetic variations is proton-pump inhibitors, for example, omeprazole,” Dr. Zajic said. Proton-pump inhibitors (PPIs) are processed by the CYP2C19 enzyme, so variants in the gene can determine how quickly the body breaks down the drug. A 2018 overview of the pharmacogenetics of PPIs published in Expert Opinion on Drug Metabolism & Toxicology estimated that about 5% of patients are ultra-rapid metabolizers of PPIs and about 27% are considered rapid metabolizers. These patients are less likely to respond to a standard dose of the drug, Dr. Zajic said.

Currently, for patients considered rapid or ultra-rapid metabolizers of PPIs based on CYP2C19 status, the Dutch Pharmacogenetics Working Group, a multidisciplinary group of pharmacists, physicians, clinical pharmacologists, chemists, epidemiologists and toxicologists, recommends a dose increase of 400% for pantoprazole, 200% for lansoprazole, 100% to 200% for omeprazole, and 50% to 100% for esomeprazole, respectively. The Clinical Pharmacogenetics Implementation Consortium (CPIC), a U.S.-based consortium, has published several guidelines about genetics and prescribing, with more in development.

The Coriell Institute for Medical Research has also recently launched a research initiative called the Camden Opioid Research Initiative to look at how genetic variants may affect several commonly prescribed opioids like tramadol or oxycodone, Dr. Zajic said. “Research is starting to show that people with certain genetic variants can have greater or worse pain relief, greater or worse side effect profiles, and greater risk for addiction,” he noted.

Body weight

Even simple factors such as weight may affect appropriate dosing of commonly used medications like antibiotics or painkillers. When prescribing these medications in pediatric populations, weight is often used to determine an appropriate dose; however, that practice is less frequent in adult populations, according to Dr. Corbert.

In 2009, Matthew E. Falagas, MD, and Drosos E. Karageorgopoulos, MD, of Alfa Institute of Biomedical Sciences in Athens, Greece, wrote a commentary in The Lancet where they questioned this one-size-fits-all approach for antimicrobial agents. In the commentary, they noted that “several physiological alterations reported in obesity can affect the processes of distribution, protein binding, metabolism, and clearance of antimicrobial agents” and concluded that “tailoring the dosing of antimicrobial agents in adults to the physical characteristics of individual patients could be an important way to achieve maximum effectiveness and safety of antimicrobial therapy.”

More recently, a study published in The Lancet in 2018 questioned the use of a one-dose-fits-all approach for aspirin in the prevention of cardiovascular events. The study pooled data from 10 clinical trials of aspirin in primary prevention and found that low-dose aspirin (75 to 100 mg) appeared to be less effective in patients who were heavier.

“Low doses seemed to be most effective at a low body weight, but that benefit was lost at a higher body weight,” said study author Peter M. Rothwell, PhD, director of the Centre for Prevention of Stroke and Dementia at the University of Oxford in England. In contrast, higher doses of aspirin reduced cardiovascular events only at a higher weight.

Race, sex

How a patient's race and sex affect drug metabolism is often unclear, according to Dr. Zajic. A 1998 Veterans Affairs study published in JAMA found that black men with hypertension did not respond as well as white men to angiotensin-converting enzyme inhibitors and beta-blockers but responded better to calcium-channel blockers and diuretics. Other potential racial differences in drug metabolism could exist but simply may not have been discovered, as many older trials of some of the most commonly used drugs did not include many, or any, nonwhite patients, explained Dr. Rothwell.

“In general, though, we have to be careful with race and ethnicity when it comes to dosing because those are social categories and not biological categories,” Dr. Zajic said. “In the absence of genetic data, those categories are being used as a proxy.”

Regarding sex, research has shown that men and women process alcohol differently, even after adjustment for body weight, and the same is true for certain drugs, Dr. Zajic said. For example, the FDA recommends lower doses of drugs containing the sleeping aid zolpidem for women than for men because women eliminate the drug from their bodies more slowly.

Ready for the clinic

According to Dr. Cobert, the medical field does not know quite enough yet to fully prescribe drugs based on genetic characteristics, but “we are getting there,” he said.

Still, clinicians should be aware of as many of these dosing differences as possible, Dr. Zajic advised.

“Sometimes people are surprised at how common some of these genetic variants are; they underestimate them,” he said. “It is not a majority of people by any stretch, but if you have a room full of people, there will be some in that room that could have improved medical care with this information.”

Plus, the relevant technology for genotyping is pretty well developed and inexpensive, Dr. Zajic added, and a number of companies offer this capability to either individuals or their doctors.

“Most of these services assay a selected set of drug metabolism [single nucleotide polymorphisms], use an algorithm to assign different metabolizer statuses for each gene, and then generate recommendations for patients,” Dr. Zajic said. Although some payers in the U.S. may be reluctant to cover such testing, it should be viewed as an investment in the future, he noted.

“A patient's DNA doesn't change over the course of their life,” he said. “We could do genetic sequencing and put the results in their medical record, and it would be useful for the rest of their life.”