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Genome BC Project Aims to Launch PGx Test to Predict Adverse Drug Reactions in Children

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As part of an ongoing pediatric pharmacogenomics project, researchers at Genome British Columbia are aiming to develop predictive tests that will help children avoid serious adverse drug reactions.

Last month, the Canadian research organization announced that project leaders Bruce Carleton, director of the Pharmaceutical Outcomes Program at Children and Women's Health Centre of British Columbia, and Michael Hayden, director of the University of British Columbia's Centre for Molecular Medicine and Therapeutics, are planning to develop genetic tests that will predict which children should avoid the oncologic cisplatin and anthracyclines in the treatment of leukemia.

Carleton and Hayden are also looking at genetic markers in new mothers treated with codeine to determine if breast feeding could lead to fatal toxicities in their babies.

The research project, called "Genotype-Specific Approaches to Therapy in Childhood: The Canadian Pharmacogenomics Network for Drug Safety" will utilize a hospital-based ADR monitoring network Carleton and Hayden have built across Canada. The researchers have already collected samples from patients who experienced adverse drug reactions reported at 10 pediatric teaching hospitals in Canada.

The researchers are taking a part candidate-gene and part genome-wide approach in designing their studies. "We have picked out candidate genes related to the specific drugs, as well as key ADME and toxicity genes associated with all drugs, because many drugs share similar metabolic pathways," Carleton told Pharmacogenomics Reporter this week.

In order to find predictive markers, researchers plan to examine 500 known functional SNPs in candidate genes to find predictive markers, will identify ADR-predictive SNPs by sequencing candidate genes, and conduct proteomic analysis.

"Furthermore, the reduced genetic heterogeneity in Canada's unique isolated founder populations (i.e., Quebec, Newfoundland, Nova Scotia) represent a tremendous opportunity for new ADR gene discovery," Genome BC states on its website.

Of these three efforts, the researchers plan to develop a predictive test for at least one drug-related toxicity. However, according to Carleton, the researchers have not yet decided which project to advance into diagnostic development.

According to Health Canada, the Canadian health regulatory body, more than 50 percent of newly launched medications have serious adverse drug reactions that show up in the post-marketing setting. More importantly, three-quarters of medications currently out on the market have not been tested in children.

The researchers chose to investigate genetic markers for adverse reactions to cisplatin, anthracyclines, and codeine in nursing mothers, based on data collected through its pediatric hospital-based ADR monitoring network. They have collected more than 2,000 ADR cases and more than 18,000 drug-matched controls in three years.

Cisplatin is the standard of care in treating solid tumors in children. According to Genome BC, approximately 1 million new patients per year receive the drug. However, the drug causes hearing loss in the majority of children who receive it.

Anthracyclines are a class of drugs used in the treatment of leukemia, but it damages the heart of 18 percent of children who take it. Approximately 1 million North American patients receive the drug each year.

The genetic risks associated with codeine to babies are particularly imminent since codeine is a widely prescribed analgesic after child birth and the American Academy of Pediatrics does not restrict nursing moms from using the analgesic. Genome BC estimates that many as 2,000 Canadian babies per year are at risk based on their genetic profiles.

Codeine "is often given as part of a routine package of pain meds for new moms, most of who are breast feeding," Carleton said. "So, if you have a particular gene variant then your baby is at risk."

In October, HealthCanada requested manufacturers of codeine-containing products to revise labeling to include information that better identifies the risk to breastfed babies whose mothers are ultra-rapid metabolizers of codeine. The health regulatory body also warned nursing mothers to consult a doctor before taking codeine-containing products, avoid over-the-counter cough or pain medications that list codeine as an ingredient, and to be watchful that after taking codeine products that their newborn baby isn't overly sleepy or has trouble breastfeeding.

The US Food and Drug Administration and the European Medicines Agency have issued similar warnings and are looking at the genetic risk markers identified by Carleton and Hayden.

"We've uncovered these genes that lead to gene variance in moms who are breast-feeding, which lead to production of morphine, the active form of codeine, in the body excreted in the breast milk," Carleton explained. "That has proven lethal to at least one baby and possibly many others. We don't know what the numbers are yet."

This project is the furthest along, according to Carleton.

The next step for the researchers is to conduct pharmacokinetic studies to validate the genetic markers they have linked to these adverse drug reactions, and to make sure that genetic tests for these indications would be clinically useful.

For pediatric clinical trials researchers must garner assent from the children and consent from their parents. However, the serious nature of the studies being conducted by Genome BC has drawn great interest and steady participation.

"We have high participation in these trials because they face a potential of a lifetime exposure risk to the same product. If it's a genetic risk then that may put their siblings at risk and even their parents," Carleton said. "There tends to be high participation because people tend to recognize that this is of benefit not only to their child, but also to their siblings and to themselves."

The GATC project was funded with a three-year $8.4 million research from Genome Canada through Genome BC. In 2006, the Pfizer Canada also gave $500,000 to the effort. According to Carleton, his research has received $10 million in funding to date, and for diagnostics development the researchers have $4.3 million.

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