Pharmacology: Zolpidem is a nonbenzodiazepine sedative-hypnotic which preferentially binds to omega-1 receptor subtype (benzodiazepine-1 or BZ1) which corresponds to the gamma aminobutyric acid (GABA)A receptor containing the α1-subunit. In contrast, benzodiazepines nonselectively bind to both omega-1 and omega-2 subtypes. The modulation of the chloride anion channel via this GABAA receptor leads to the specific sedative effects of zolpidem.
In humans, zolpidem decreases sleep latency and the number of awakenings, and increases sleep duration and sleep quality. These effects are associated with a characteristic electroencephalogram (EEG) profile, different from that of the benzodiazepines. In studies that measured the percentage of time spent in each sleep stage, zolpidem has generally been shown to preserve sleep stages. At the recommended dose, zolpidem has no influence on the paradoxical sleep duration (rapid eye movement or REM). The preservation of deep sleep (stages 3 and 4 slow-wave sleep) may be explained by the selective omega-1 binding by zolpidem.
The selectivity of zolpidem for BZ1 receptors is thought to be responsible for its greater potency as a sedative-hypnotic as opposed to an anticonvulsant muscle relaxant agent. The properties of zolpidem can be summarized as: sedative>anticonvulsant>muscle relaxant. This contrasts with those of benzodiazepines, which can be represented as anticonvulsant>muscle relaxant>sedative.
Pharmacokinetics: Zolpidem tartrate bioavailability is about 70% following oral administration and demonstrates linear kinetics in the therapeutic dose range of 5 to 20 mg. The peak plasma concentration (Cmax) is reached at 0.5 to 3 hours.
A food effect study showed that with food, mean area under the curve (AUC) and Cmax were decreased by 15% and 25%, respectively, while mean time to reach max plasma concentration (Tmax) was prolonged by 60% (from 1.4 to 2.2 hours). The half-life remained unchanged. This study showed that for faster sleep onset, zolpidem should not be given with or immediately after a meal.
Total protein binding was found to be 92.5±0.1% and remained constant; independent of concentration between 40 and 790 ng/mL. The volume of distribution is 0.54±0.02 L/kg. Zolpidem tartrate did not accumulate in young adults following nightly dosing of 20 mg tablets for two weeks.
Zolpidem tartrate is metabolized in the liver via oxidation and hydroxylation, principally by CYP3A4 and to a lesser extent by CYP1A2 and CYP2D6. It has no active metabolites. A moderate amount of the drug is subject to first-pass metabolism (~30%).
Zolpidem tartrate plasma elimination half-life (t1/2) is approximately 2.4 hours and with duration of action of up to six hours. Zolpidem tartrate is eliminated entirely by hepatic metabolism to inactive metabolites, mainly in the urine (56%) and in the feces (37%). It does not have an inducer effect on hepatic enzymes.
Special Population: Elderly: Zolpidem tartrate mean Cmax, t1/2, and AUC were significantly increased in the elderly compared to young adults. Zolpidem tartrate did not accumulate in elderly subjects following nightly oral dosing of 10 mg for one week.
Hepatic Impairment: After a single 20 mg oral zolpidem tartrate dose, mean Cmax and AUC were found to be two times (250 vs 499 ng/mL) and five times (788 vs 4,203 ng.hr/mL) higher, respectively, in hepatically-compromised patients. Tmax did not change. The mean t1/2 in cirrhotic patients of 9.9 hours was greater than that observed in normal subjects of 2.2 hours. Dosing should be adjusted in patients with hepatic insufficiency.
Renal Impairment: No statistically significant differences were observed for Cmax, Tmax, t1/2, and AUC between the first and last of drug administration when baseline concentration adjustments were made. No accumulation of unchanged drug appeared after 14 or 21 days. Zolpidem tartrate pharmacokinetics were not significantly different in renally impaired patients. Dosage adjustment is not recommended.
Gender: Women clear zolpidem tartrate from the body at a lower rate than men. Cmax and AUC parameters of zolpidem were approximately 45% higher at the same dose in female subjects compared with male subjects. In geriatric patients, clearance of zolpidem tartrate is similar in men and women.