In medicine, one dose doesn’t fit all


I Ioften use sleeping pills containing zolpidem (Ambien is the predominant brand-name version) to help reset my biological clock when I travel across time zones, or if I just have trouble getting to sleep. And I’m not alone. Doctors wrote about 40 million prescriptions for it in 2012.

Although this drug has been around and used extensively for two decades, it was not until

January that the U.S. Food and Drug Administration got around to recommending that women should receive a lower dose of zolpidem than men — 5 milligrams instead of the standard 10. The reason is that as long as eight hours after taking it, women may have unacceptably high blood levels of zolpidem that can impair driving and other activities that require alertness (three to five times more frequently than men).

Doctors have known for a long time that although zolpidem is, overall, quite safe and effective, it can have side effects, including drowsiness while driving and elaborate sleepwalking episodes that patients can’t recall.


Gender-specific differences in the recommended dose of zolpidem should not come as a surprise to the medical community. There are, after all, other population subgroups for whom dosage adjustments of various medicines are needed: Aging, for example, causes important variations in responses to drugs.

For several reasons, older patients are far more likely to experience adverse drug reactions. For one thing, on average they take a larger number of drugs than younger people, which increases the likelihood that two or more will interact in a harmful way. Also, clearance by the kidneys and liver — the two most important routes for the elimination of drugs — is reduced. As people age, these organs get less blood flow, and there is diminished activity of the hepatic enzymes that metabolize drugs.

Another interesting age-related anomaly concerns a decrease in total body water and a relative increase in body fat. (And women have a higher percentage of body fat than men.) Because of these changes, water-soluble drugs become more concentrated in the blood, and fat-soluble drugs have longer half-lives.

Moreover, serum protein levels are decreased in the elderly (especially if they’re sick), which reduces the protein binding capacity of the blood and leaves more free — that is, active — drug circulating. And yet, surprisingly few physicians routinely reduce drug dosages in older patients.

Similarly, there is wide variation in the ability of various ethnic groups and individuals to clear medications from the bloodstream because of differences in the activity of the enzymes that metabolize, or degrade, drugs. For that reason, drug safety and efficacy are affected by differences in the genes that code for these enzymes. One genetic locus, for example, is responsible for the enzymes that degrade as much as 20% of commonly prescribed drugs. In the population, there are a large number of variants of this family of genes, some of which produce enzymes that perform poorly.

This phenomenon is important because (with the exception of drugs that must be converted in the body from an inactive to an active form) individuals with low-metabolizing enzymes clear certain drugs slowly and have more medication in their blood for longer periods than those with high-metabolizing ones.


To ensure that the cure isn’t worse than the disease, regulators, medical professionals and patients need to be aware of the spectrum of individuals’ responses to drugs, especially for those medicines that have a narrow therapeutic range or that can cause serious side effects when the levels are too high. To minimize adverse reactions, it is often prudent to start a new drug at a very low dose and to increase it until the desired effect is achieved.

Henry I. Miller is a physician and a fellow at Stanford University’s Hoover Institution. He was the founding director of the Office of Biotechnology at the FDA.