Gender difference in zolpidem pharmacology has clinical consequences

By Will Boggs MD

NEW YORK (Reuters Health) - Women display lower clearance and greater effects of the commonly used sedative zolpidem following sublingual administration, compared with men, according to a study in healthy volunteers.

At least four other studies have demonstrated lower clearance of zolpidem in non-elderly women, but it remains unclear whether the consequences are clinically significant. Still, the US Food and Drug Administration has mandated 50% lower maximum doses for women than for men.

Dr. David J. Greenblatt from Tufts University School of Medicine, Boston, Massachusetts and colleagues evaluated the influence of gender on pharmacokinetics and pharmacodynamics of sublingual zolpidem in a crossover study of 11 healthy women and 13 healthy men.

Compared with men, women had consistently higher plasma zolpidem concentrations, maximum concentration per dose, and total AUC per dose, as well as significantly lower clearance. Gender did not affect zolpidem half-life.

Among men, there was a dose-related effect on sedation, whereas for women, dose significantly influenced results of the Digit Symbol Substitution Test, Choice Reaction Test response time and lapses, and Symbol Copying Test.

None of the pharmacodynamics effect areas differed significantly from zero for male subjects, the authors reported in this month's print issue of The Journal of Clinical Pharmacology.

For female subjects, though, the pharmacodynamics effects for all tests differed significantly from zero for both zolpidem doses (1.75 and 3.5 mg), but only in aggregated data (i.e., not within individuals). By four to five hours after dosing, these effects had returned to baseline, regardless of dosage.

"The greater pharmacodynamics effects of zolpidem in female subjects were partly explained by the higher plasma zolpidem concentrations in females," the researchers note. "However, some component of the greater response in females may be explained by other factors, such as increased intrinsic sensitivity among female subjects."

"Clinical and epidemiologic data do not provide a signal to indicate that the higher plasma concentrations of zolpidem in women are associated with an increased risk of adverse reactions," they conclude. "Nonetheless, the approved label for zolpidem indicates a zolpidem dosage of 3.5 mg for adult non-elderly men and 1.75 mg for adult non-elderly women."

Dr. Joris C. Verster from Utrecht University in The Netherlands has also studied zolpidem pharmacology. He told Reuters Health, "Women metabolize zolpidem more slowly than men, and therefore may show greater drug effects."

"It seems that some women will need the higher dose and others will need the lower dose," Dr. Verster said. "The recommended starting dose for all zolpidem products is lower in women than in men. We rely on clinicians to titrate appropriately."

Dr. Verster added, "In a recent Dutch study, on-road driving ability was examined, four hours after middle of the night administration of 3.5 mg sublingual zolpidem. No significant impairment was found on next-morning driving performance. Although men and women in this study both received the same dose of zolpidem (3.5 mg), no significant gender differences were found on driving performance."

Transcept Pharmaceuticals, Inc. and PurduePharma, which market zolpidem as Intermezzo, sponsored the study and employed five of the eight authors. Two other authors reported consulting or advisory relationships with Transcept.

The drug is also sold as Ambien, by Sanofi-Aventis.

Dr. Greenblatt declined a request for comments.

SOURCE: http://bit.ly/1o1jsax

J Clin Pharmacol 2014;54:282-290.

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