Personal Best

Pharmacists provide a wide range of critical health-care services.  But pharmacy, like most health care, is changing to accommodate the needs of the community and to adapt to the latest scientific research. Case in point: there’s an emerging field that personalizes drug dosing based on a patient’s DNA profile. It’s called pharmacogenomics and researchers at the U of A are leaders in this emerging field.

“Pharmacogenomics is the study of using patients’ genetic profiles to tailor dosing for optimizing results and reducing side-effects,” explains Tony Kiang, researcher and associate professor (as of July 2023) in the Faculty of Pharmacy and Pharmaceutical Sciences at the U of A. 

Currently, medication is prescribed and dosages are determined based on what is recommended by empirical studies and what works for the average population. This framework is generic and has its limitations. 

“People respond to drugs differently,” Kiang says. “It doesn’t make sense that we’d all get the same dose or medication.” Pharmacists and doctors already take into account some key factors when prescribing and dosing — weight and age, for example, and in some cases, sex. 

But identifying genetic information — say, a gene that creates enzymes that affect how your body metabolizes a drug — could be another helpful factor in determining effective dosages and medications for patients. People with a genetic predisposition to metabolizing a drug slowly may need less of the medication as it would remain in the system longer. People with a genetic predisposition to metabolizing a drug faster might need more of the drug. Also, a DNA profile can inform which medications might be more or less effective for a particular individual. There’s a lot of research underway that explores the potential of pharmacogenomic practices with drugs such as immunosuppressants and antidepressants. 

THE PUZZLE OF VARIABLE SIDE-EFFECTS

Kiang and his student crew at the university lab are particularly concerned about the side-effects stemming from immunosuppressant drugs used for kidney transplant patients and are conducting pharmacogenomic research to reduce toxicity and enhance efficacy. 

A recent study looked at an immunosuppressant drug called mycophenolic acid (MPA). This is a common anti-rejection drug that patients take after transplant, but it can come with side-effects such as stomach upset, dizziness and neutropenia (low white cell counts). Kiang theorized that kidney transplant patients who developed neutropenia would have higher MPA exposure than patients without neutropenia. Further, he hypothesized that metabolism and transporter genes might be responsible for this disposition. He tracked 21 patients — via blood work — at one month, three months and 12 months, measuring levels of MPA and neutropenia. He found that an inverse relationship existed between normalized exposure of MPA and neutrophil counts (when MPA cleared normally, there was less toxicity). And he found some alterations in the minor allele frequencies of drug metabolism and transporter genes in this patient population that warrant further research. These results speak to the importance of monitoring the use of MPA in kidney transplant patients. Down the road, this kind of genetic reason for the way patients metabolize MPA could inform dose — and outcome — for patients.  

Kiang and his research team also looked at bacteria in the gut that generate toxins and affect metabolism. A healthy person is able to clear gut bacteria toxins, but kidney transplant patients may not be able to because of reduced kidney function. Here’s how it worked: Kiang’s team looked at engineered enzyme samples from both normal and dysfunctional genes and found three key discoveries. First, the enzyme responsible for the creation of p-cresol sulfate (a toxin) was SULT1A1. Second, dysfunctional copies of the SULT1A1 enzyme led to reduced production of the toxin. Third, mefenamic acid was able to reduce the production of the toxin from the system. But so what?

Well, these findings suggest that patients with kidney disease might be affected by high toxin levels and might benefit from the monitoring of SULT1A1 activities. Perhaps genetic testing for this particular enzyme in the future could help predict which patients may have high or low toxin levels. Kiang’s lab also discovered a potential therapeutic agent that could reduce toxin levels. Kiang’s studies are funded by national foundation grants and Tri-Council grants.    

“But pharmacogenomics isn’t yet common practice in Canada,” explains Kiang. “With the majority of medications, genomics is not used for dosing. Before you change a dosing strategy, you need to do extensive scientific research to prove that the strategy works.” 

That means more work along the lines of what Kiang and his research team are doing: identifying genes responsible for metabolizing a medication and identifying variations in those genes and associated enzymes, which might influence metabolism; testing that theory to see if differences in dosages result in better outcomes; and then moving on to larger randomized, double-blind clinical trials. This process is conducted drug by drug, before Health Canada approves adjusting dosages. 

“Health Canada has to screen the data and weigh benefits versus conventional dosages. It’s a long process,” Kiang says. “It will be a few more years before pharmacogenomics enters the mainstream.” But novel research happening in Kiang’s lab now may be mainstream in the future. Processes have to be in place to get there.

In tandem with identifying genes and enzymes that affect metabolism, broad and speedy access to genotyping is necessary. That’s where a patient’s DNA is retrieved and assessed for genetic information to tailor drug dosing. This process varies depending on the sample used, the technology used and the cost. Currently, people in Alberta who are interested in getting their DNA sequenced must pay. 

“There will be costs associated with broad-scale genotyping — the technology, the training, the lab work — but these could lead to bigger savings to the health-care system if the paradigm works,” says Kiang. There’ll be fewer negative side-effects from medications with a tailored dosing and fewer trips to the hospital emergency department after a bad reaction, Kiang predicts. The goal would be for genotyping to be publicly funded, accessible to all and an integral part of Canada’s universal health care. He’s not the only one who’s hopeful.

THE PROMISE OF AVOIDING TRIAL AND ERROR

Lisa Guirguis, ’97 BSc(Pharm), ’00 MSc, is also at the forefront of pharmacogenomics research. She’s a researcher and pharmacist as well as an associate professor in the faculty. Her focus is innovation and the uptake of new technologies in pharmacy practice. She is particularly interested in how pharmacogenomics can be used to address issues with antidepressant medication.

“Depression is widely seen and managed in the community but — in some patients — it can be hard to treat. With pharmacogenomics, we have the tools to assess which drugs won’t work for you and which will likely work based on your genetic code,” she explains. “And patients have a right to know these tests are available.” 

But there is a disconnect: most pharmacists, clinicians and patients don’t know this kind of testing is available. That is what drives Guirguis. “I have a moral imperative to put these tools in the public domain.”

In fall 2021, she and her research team conducted a comprehensive literature review, focusing on pharmacogenomics and community pharmacy, to determine what data existed in the field and to assess if the research was evolving. Early studies were about awareness (there was little); recent studies reported positive outcomes for patients with pharmacogenomic testing. “The research is going in the right direction,” she says.

Guirguis’s team is now doing interviews with pharmacists in Alberta to generate quantitative and qualitative information about the use of pharmacogenomics in community pharmacy, with funding from the Margaret and Andrew Stephens Family Foundation. So far, pharmacists appear invested. They report that they’re teaching themselves how to use and interpret the technology. And they say that success stories of patients who’ve realized improvement in their quality of life due to pharmacogenomics have been the biggest factor in requests for testing. “Finally, pharmacogenomics has helped patients find medication that improves their mental health,” says Guirguis.

These discussions also include looking at what shared decision-making tools pharmacists can use to hold clear and honest conversations with patients about pharmacogenomics.  “We have the technology and we have the science,” she says. The next step is to plan a path to access, interpretation and clear communication with patients.   

It won’t be an easy road; Guirguis estimates less than five per cent of Albertans using antidepressant medication are incorporating pharmacogenomics today. But she is in it for the long haul. “We need to develop solutions that are scalable in the community,” she says. “And we need to get this publicly funded. Often the people who need this most are least able to afford it.” 

RESEARCH AND APPLICATION 

In addition to the work of researchers and educators like Kiang and Guirguis, other stakeholders are key to moving the technology and science into broad pharmaceutical practice. Pharmacy students will need to be receptive to theoretical information, practical training and a new approach to doing their jobs. Governments and other funders will need to provide money for state-of-the art research, equipment and genotyping. Clinicians will need to learn how to interpret ever-changing data and be prepared to create space to have those conversations with patients about the benefits of dosing differently. Finally, patients will need to be on board with participating in clinical trials and — when we get to that point — providing their own DNA samples for tailored dosing at their local pharmacy. 

New technology brings questions. How do we handle consent regarding DNA retrieval? What about minors or people who are vulnerable? How will companies, government and clinicians use these samples respectfully and responsibly, respecting a patient’s privacy? And how will clinicians have honest, plain-language conversations with patients about the benefits and risks? For example, you could be “genetically neutral.” That is, neither one drug nor another is known to be more beneficial, which could be deflating, says Guirguis.

Pharmacogenomics is in its infancy. But down the road, it’s likely you will have the option of walking into your local pharmacy with a prescription that will have your genetic profile attached. After all, DNA only needs to be retrieved once and, in an ideal world, this could happen at your community lab, along with blood work and a urinalysis test. Your pharmacist could then give you a specific medication and dosage based specifically on your DNA profile.  

As promising as pharmacogenomics is, it will remain a single tool in the clinician’s toolbox. “Clinicians will still need to monitor the patients closely for side-effects and efficacy. It is a great start, personalized genomic dosing, but it should complement current clinical practices,” says Kiang. “It’s just the beginning.” 

But it is a bright beginning, he admits. “It’ll take a while before cars will fly in the sky, but it is possible. It’s important that we still support robust research and focus on quality of care for patients. That’s the reason why we are doing this.”  

This story is from the Winter edition of The Mortar & Pestle Magazine.