Pharmacogenomics and drug safety

New drugs go through clinical trials before they can be marketed. Phase I trials are for safety. Phase II/III trials are for efficacy. If a drug fails these trials, it can’t be sold.

One challenge to drug testing is trial enrollment. Ideally, the subjects should be demographically representative. The problem is that there can be significant variation among trial participants that is not reflected in sex, age or ethnicity.

Drugs have a half-life in the body—they are eventually excreted. Some people are born with a genetic makeup that makes them “fast metabolizers” or “slow metabolizers.” Fast metabolizers may achieve lower steady-state levels of the drug in their bodies for a given dosage, making it look like the drug isn’t working. Slow metabolizers may experience toxicity as drug accumulates in the body faster than it can be processed. Failing to screen for drug metabolism in clinical trial subjects may result in the drug failing the trial, when it really was effective for a sub-population. Failing to screen for drug metabolism in the cancer clinic could result in either ineffective dosing or lethal dosing.

An example of this is 5-fluorouracil (5-FU) or capecitabine chemotherapy for cancer.

“One January morning in 2021, Carol Rosen took a standard treatment for metastatic breast cancer. Three gruesome weeks later, she died in excruciating pain from the very drug meant to prolong her life.

“Rosen, a 70-year-old retired schoolteacher, passed her final days in anguish, enduring severe diarrhea and nausea and terrible sores in her mouth that kept her from eating, drinking, and, eventually, speaking. Skin peeled off her body. Her kidneys and liver failed. “Your body burns from the inside out,” said Rosen’s daughter, Lindsay Murray, of Andover, Massachusetts.

“Rosen was one of more than 275,000 cancer patients in the U.S. who are infused each year with fluorouracil, known as 5-FU, or, as in Rosen’s case, take a nearly identical drug in pill form called capecitabine. These common types of chemotherapy are no picnic for anyone, but for patients who are deficient in an enzyme that metabolizes the drugs, they can be torturous or deadly.

Those patients essentially overdose because the drugs stay in the body for hours rather than being quickly metabolized and excreted. The drugs kill an estimated one in 1,000 patients who take them – hundreds each year — and severely sicken or hospitalize one in 50. Doctors can test for the deficiency and get results within a week — and then either switch drugs or lower the dosage if patients have a genetic variant that carries risk.

“Yet a recent survey found that only 3% of U.S. oncologists routinely order the tests before dosing patients with 5-FU or capecitabine.”

Thanks to the human genome project, the field of pharmacogenomics—the branch of genetics concerned with how individual’s genetics affect the response to therapeutic drugs—was born. Pharmacogenomic testing before dosing can save lives in the clinic and could salvage drugs in clinical trials.

pharmacogenomics for cancer chemotherapy and drug screening