Zolpidem pharmacokinetics and molecular data

Pharmacokinetics
Mechanism Food effect Effect on hepatic system Effect on renal system
 * Elderly

Mechanism
The pharmacokinetic profile of Zolpidem tartrate tablets is characterized by rapid absorption from the GI tract and a short elimination half-life (T1/2) in healthy subjects. In a single-dose crossover study in 45 healthy subjects administered 5 and 10 mg Zolpidem tartrate tablets, the mean peak concentrations (Cmax) were 59 (range: 29 to 113) and 121 (range: 58 to 272) ng/mL, respectively, occurring at a mean time (Tmax) of 1.6 hours for both. The mean Zolpidem tartrate tablets elimination half-life was 2.6 (range: 1.4 to 4.5) and 2.5 (range: 1.4 to 3.8) hours, for the 5 and 10 mg tablets, respectively. Zolpidem tartrate tablets are converted to inactive metabolites that are eliminated primarily by renal excretion. Zolpidem tartrate tablets demonstrated linear kinetics in the dose range of 5 to 20 mg. Total protein binding was found to be 92.5 ± 0.1% and remained constant, independent of concentration between 40 and 790 ng/mL. Zolpidem did not accumulate in young adults following nightly dosing with 20 mg Zolpidem tartrate tablets for 2 weeks. Return to top

Food effect
A food-effect study in 30 healthy male volunteers compared the pharmacokinetics of Zolpidem tartrate tablets 10 mg when administered while fasting or 20 minutes after a meal. Results demonstrated that with food, mean AUC and Cmax were decreased by 15% and 25%, respectively, while mean Tmax was prolonged by 60% (from 1.4 to 2.2 hr). The half-life remained unchanged. These results suggest that, for faster sleep onset, Zolpidem tartrate tablets should not be administered with or immediately after a meal. Return to top

Elderly
In the elderly, the dose for Zolpidem tartrate tablets should be 5 mg. This recommendation is based on several studies in which the mean Cmax, T1/2, and AUC were significantly increased when compared to results in young adults. In one study of eight elderly subjects (>70 years), the means for Cmax, T1/2, and AUC significantly increased by 50% (255 vs 384 ng/mL), 32% (2.2 vs 2.9 hr), and 64% (955 vs 1,562 ng•hr/mL), respectively, as compared to younger adults (20 to 40 years) following a single 20 mg oral dose. Zolpidem tartrate tablets do not accumulate in elderly subjects following nightly oral dosing of 10 mg for 1 week. Return to top

Effect on hepatic system
The pharmacokinetics of Zolpidem tartrate tablets in eight patients with chronic hepatic insufficiency were compared to results in healthy subjects. Following a single 20 mg oral Zolpidem 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 half-life in cirrhotic patients of 9.9 hr (range: 4.1 to 25.8 hr) was greater than that observed in normals of 2.2 hr (range: 1.6 to 2.4 hr). Dosing should be modified accordingly in patients with hepatic insufficiency. Return to top

Effect on renal system
The pharmacokinetics of Zolpidem tartrate were studied in 11 patients with endstage renal failure (mean ClCr = 6.5 ± 1.5 mL/min) undergoing hemodialysis three times a week, who were dosed with Zolpidem 10 mg orally each day for 14 or 21 days. No statistically significant differences were observed for Cmax, Tmax, half-life, and AUC between the first and last day of drug administration when baseline concentration adjustments were made. On day 1, Cmax was 172 ± 29 ng/mL (range: 46 to 344 ng/mL). After repeated dosing for 14 or 21 days, Cmax was 203 ± 32 ng/mL (range: 28 to 316 ng/mL). On day 1, Tmax was 1.7 ± 0.3 hr (range: 0.5 to 3.0 hr); after repeated dosing Tmax was 0.8 ± 0.2 hr (range: 0.5 to 2.0 hr). This variation is accounted for by noting that last-day serum sampling began 10 hours after the previous dose, rather than after 24 hours. This resulted in residual drug concentration and a shorter period to reach maximal serum concentration. On day 1, T1/2 was 2.4 ± 0.4 hr (range: 0.4 to 5.1 hr). After repeated dosing, T1/2 was 2.5 ± 0.4 hr (range: 0.7 to 4.2 hr). AUC was 796 ± 159 ng•hr/mL after the first dose and 818 ± 170 ng•hr/mL after repeated dosing. Zolpidem was not hemodialyzable. No accumulation of unchanged drug appeared after 14 or 21 days. Zolpidem tartrate tablet pharmacokinetics were not significantly different in renally impaired patients. No dosage adjustment is necessary in patients with compromised renal function. As a general precaution, these patients should be closely monitored. Return to top