Medical Examiner

The Best of Times, the Worst of Times

When during the day should you take your medication? Good question.

Chronobiologist Franz Halberg

It takes more than $800 million and 10 years to develop a new drug. Researchers perform study after study, testing a potential new medicine in cell cultures, animals, and humans. They determine whether it treats the right problem safely; should be taken orally, nasally, intravenously, or intramuscularly; and set minimum and maximum doses. But most drug trials ignore a question that increasingly seems crucial: When is the best time of day to take a given medication?

Modern drug development generally assumes that the body maintains a stable internal state. To that end, many prescription drugs are designed to be taken in equal amounts at regular intervals to keep a patient’s drug levels steady. The problem is that a growing body of research suggests that our bodies are not constant. Instead, nearly every physiological process oscillates with our internal circadian rhythms. The body’s temperature, immune function, and hormone levels all partly depend on whether it’s night or day, or sometime in between. Meanwhile, many diseases also have daily rhythms, with symptoms more severe at certain times.

The body’s sensitivity to time of day means that a drug proven safe to take in the morning may not be safe at night, or that a dose that works at 8 p.m. may be too small at 8 a.m. Some of the first—and still most compelling—evidence for these time-related differences came from Franz Halberg, widely considered to be the father of chronobiology. In a 1959 experiment that became a classic in the field,Halberg showed that it was easier for mice to survive a toxic dose of ethanol at one time of day than at another. Since then, time of day has proven to be an important factor in the safety and effectiveness of drugs for asthma, high blood pressure, and other conditions.These principles even apply to run-of-the-mill pills like aspirin, which does less damage to the stomach lining when taken in the evening than in the morning. (Conveniently, aspirin is also better at reducing blood pressure when taken before bed.)

Despite this evidence of variation, drug research is almost always done during daylight hours, when the humans leading the studies are awake and alert. And in the animal testing stage, it’s almost always done with mice and rats, which are nocturnal—the middle of ourdayis the middle of their night. This can lead to gross misestimations of the effectiveness and toxicity of a drug intended for humans. “How much time, effort and money have been wasted in this way we shall probably never know,” chronobiologistJosephine Arendt wrote in her 1998 overview of biological rhythms and medicine.

Things do get better, chronobiologically speaking, when drugs are eventually tested in humans, but only slightly so. The FDA requires three phases of clinical trials in humans before a new medicine can go on the market, but it does not require the testing of new compounds at multiple times of day. Instead, most clinical trials control for time of day. Which means that rather than assessing whether the effects of an experimental drug vary over the course of a day, the trials ensure that all patients take the drug in lockstep. When a drug is finally approved, the prescribing information issued by the FDA either contains no recommendation for what time of day patients should take it or directs patients to take it at whatever time was chosen for clinical trials, says Michael Smolensky, a chronobiologist at the University of Texas Health Sciences Center in Houston.And then, once the drug is on the market, a patient may decide to take a once-a-day drug at night, instead of in the morning, when it was tested—and experience side effects that neither the FDA nor the pharmaceutical companies anticipated.

Chronobiologists have tried—and failed—to change all of this. Several decades ago,Halberg led a delegation of scientists who met with FDA officials. “We recommended to the FDA commissioner that timing as well as dosing be considered in the administration of medications by a requirement in the package insert,” Halberg wrote in a 2003 recounting of this effort. “The commissioner explicitly assured the delegation he would do something about it.” But according to an assistant FDA commissioner who was a chronobiologist, Halberg says, after the delegation left, “the commissioner told the staff no more than to proceed with ‘business as usual.’ ”

It doesn’t help the chronobiologists’ cause that they represent a small research niche in a mammoth industry.Unless drug companies think there’s serious money at stake, they’re unlikely to poke around in the lab just to see whether a new medication has time-related effects. Drug trials that consider chronobiology would be more complex and require more patients than the status quo. What’s more, most medical professionals simply aren’t aware of the extent to which the body’s rhythms influence its response to medicine, Smolensky says. “There is no active conspiracy against chronomedicine,” he writes in his book The Body Clock Guide to Better Health. “The biggest barrier is simply inertia.”

Yet there are relatively easy ways to address the issue.Research has shown that nocturnal animals can reverse their usual biological rhythms if the rooms in which they are housed are kept relatively dark during the day and lighter at night. Drug studies should, at the very least, use animals on this adjusted schedule. Better yet, they could use two groups of rodents, a standard nocturnal set and another one on a reverse schedule. That way, scientists would be able to notice early on whether time affects how a drug works.

When it comes to human testing, the FDA could mandate small, early stage clinical trials with different groups of patients taking a drug at least three different times of day. If a certain drug turns out to have no time-related differences, we’ll be reassured that it’s safe to take anytime. Nobody knows precisely how many drugs exhibit time-related effects, but the number isn’t tiny. Many different kinds of medications behave this way, and how important the variations are depends on factors like the seriousness of the illness being treated and the side effects of the medication.

Yes, these changes will require drug trials that are larger and more costly. But the return on investment could be huge in some areas. For instance, doctors have already successfully begun integrating circadian rhythms into cancer treatment. Chemotherapy causes its famously debilitating side effects because the drugs used are highly toxic to healthy as well as cancerous cells. It turns out, however, that based on the circadian rhythm, doctors can administer chemo at a time when malignant cells are more susceptible to the drugs than normal ones are. Such carefully timed treatment has been shown to help patients tolerate higher doses of chemo and survive longer. Cancer has become one of chronomedicine’s biggest success stories. When will we hear about the next one? The clock is ticking.