Personalized Drug Therapy

By David Kattenburg

Have you ever popped the recommended dose of an over-the-counter analgesic, and it did absolutely nothing? Or a double dose did squat?

Sorely in need of shut-eye, perhaps you downed half of what the small print on a sleep medication bottle told you to, and it knocked you out for twelve hours.

Or perhaps you’re one of the truly unlucky ones, and suffered a life-threatening adverse reaction from a perfectly ordinary pill that doesn’t bother anyone else. If so, you’re in large company. Adverse drug reactions (ADRs) — the rare, unintended and harmful effects of routinely prescribed or over-the-counter drugs — are among the leading causes of death in North America.

Some 200,000 Canadians fall prey to ADRs each year, and 10,000 die, at a cost of over $13 billion to Canada’s health care system.

Thanks to modern genomics, the study of the human genome and its expression, our understanding of ADRs has advanced by leaps and bounds. Indeed, an entire field has sprung up: pharmacogenomics — the study of how genes control or influence drug action.

Dr. Colin Ross

There’s hardly a facet of drug action that isn’t determined in some way by our DNA. Before drugs reach their “site of action” somewhere in our body, they must first be absorbed by our underlying tissues. If taken orally, they pass from digestive tract to the liver, where they’re likely to be “biotransformed” — perhaps into something less potent; perhaps into something toxic. Drugs bind to proteins in the blood, and are transported through the body. Eventually they get excreted by the kidneys.

At each step in this long journey between a drug’s absorption and its excretion (a drug’s pharmacokinetics), a host of proteins (coded for by genes) play key roles in determining how it will act.

Then there’s the “pharmacodynamics” part — how drugs actually work; their mechanism of action. Here again, it’s our genes that call the shots. No wonder human responses to drugs vary so enormously.

Evaluating the wide range of individual responses to drugs, surveillance for adverse reactions, and improving drug safety are the focus of the Canadian Pharmacogenomics Network for Drug Safety. Among the CPNDS’s most groundbreaking studies are those involving pediatric medications, or adult medications that can be harmful to infants. These include:

• Findings on the harmful effect of codeine-based pain medications on breastfeeding infants; some women carry a gene that converts codeine into toxic morphine.
• The underlying genetic cause of hearing loss among children taking the platinum-based anti-cancer drug cisplatin.
• Cardiotoxicity (damage to the heart) caused by the anti-cancer drug anthracycline. 

Dr. Rod Rassekh

On a recent trip to Vancouver, I spoke with one of the CPNDS’s Principal Investigators, Dr. Bruce Carleton, with team geneticist Dr. Colin Ross, and with clinician/researcher Dr. Rod Rassekh. Listen to them here. Click on the audio link above, or download the podcast version here.

Dr. Bruce Carleton