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
This would seem a situation where the word “sex” would likely be a superior one to “gender”. There might be a few situations where the safety and effectiveness of a drug correlated with gender, but sex seems a much more likely category.
@Eric,
Fair enough. I edited it, so that it doesn’t distract from the actual subject of the post.
One month ago, I was in the hospital for something which may (or may not) have been precipitated by a combination of side effects from a new BP medication they were ramping up and a previously unknown allergy to a medication I had just stopped using, delayed allergic reactions being well documented. A one-of.
At the same time I am in a demographic (old, multiple chronic conditions) that rarely would show up in a clinical trial, even if I were not deliberately omitted because of one or more conditions. That means I really have to check anything new they want to give me, because works and is safe to use for the “normal” population does not mean it is safe or effective on me.
At least they are trying to include more types of people than before, but people are always a type of their own besides. I know I do not react to some drugs the way most people would. When it says may make you drowsy, about 10% time it gets me wired up and unable to sleep. Okay.
Case in point, the Covid-19 vaccines. Thousands of people in the various trials, approved as safe to use, and almost the first person to get it has an anaphylactic reaction. Not something that could have been anticipated based on the trials.
Some of the new techniques to modify the patient’s own cells may eliminate some of the hit-or-miss on finding what will work and what will harm before it happens. Hope so.
@Jane,
I enrolled in the Moderna vaccine Phase III trial in August 2020. I was 65 and they were delighted to have a geriatric patient! I was happy to be in the vaccine arm of the trial, which I knew within 12 hrs of getting the booster.
Recruiting for drug trials is surprisingly difficult. Drug companies have to work through hospitals and clinics, and they have to sign up patients that meet particular criteria. They have to have the disease in question. They have to have a relevant variant, perhaps one that has already resisted treatment. There has to be some diversity in the sample. They have to give their informed consent. They have to be willing to open their medical records and do any appropriate follow through as some trials run for years.
I would guess those 3% of oncologists who don’t do the testing described are sitting in the waiting room for those receiving malpractice suits.
@Jack,
You misread the post:
“Yet a recent survey found that only 3% of U.S. oncologists routinely order the tests before dosing patients with 5-FU or capecitabine.”
Not 3% who don’t. 3% who do.