ZALEPLON

ZALEPLON — zaleplon capsule
Physicians Total Care, Inc.

DESCRIPTION

Zaleplon is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. The chemical name of zaleplon is N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide. Its molecular formula is C17 H15 N5 O, and its molecular weight is 305.34. The structural formula is shown below.

Chemical Structure

Zaleplon is a white to light pale yellow, crystalline powder that is practically insoluble in water and sparingly soluble in alcohol or propylene glycol. Its partition coefficient in octanol/water is constant (log PC = 1.23) over the pH range of 1 to 7.

CLINICAL PHARMACOLOGY

Pharmacodynamics and Mechanism of Action

While zaleplon is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it interacts with the gamma-aminobutyric acid-benzodiazepine (GABA-BZ) receptor complex. Subunit modulation of the GABA-BZ receptor chloride channel macromolecular complex is hypothesized to be responsible for some of the pharmacological properties of benzodiazepines, which include sedative, anxiolytic, muscle relaxant, and anticonvulsive effects in animal models.

A /chloride ion channel receptor complex and potentiates t-butyl-bicyclophosphorothionate (TBPS) binding. Studies of binding of zaleplon to recombinant GABAA receptors (α1 β1 γ2 [omega-1] and α2 β1 γ2 [omega-2]) have shown that zaleplon has a low affinity for these receptors, with preferential binding to the omega-1 receptor.

Pharmacokinetics

The pharmacokinetics of zaleplon have been investigated in more than 500 healthy subjects (young and elderly), nursing mothers, and patients with hepatic disease or renal disease. In healthy subjects, the pharmacokinetic profile has been examined after single doses of up to 60 mg and once-daily administration at 15 mg and 30 mg for 10 days. Zaleplon was rapidly absorbed with a time to peak concentration (tmax ) of approximately 1 hour and a terminal-phase elimination half-life (t1/2 ) of approximately 1 hour. Zaleplon does not accumulate with once-daily administration and its pharmacokinetics are dose proportional in the therapeutic range.

Absorption

Zaleplon is rapidly and almost completely absorbed following oral administration. Peak plasma concentrations are attained within approximately 1 hour after oral administration. Although zaleplon is well absorbed, its absolute bioavailability is approximately 30% because it undergoes significant presystemic metabolism.

Distribution

Zaleplon is a lipophilic compound with a volume of distribution of approximately 1.4 L/kg following intravenous (IV) administration, indicating substantial distribution into extravascular tissues. The in vitro plasma protein binding is approximately 60% ± 15% and is independent of zaleplon concentration over the range of 10 ng/mL to 1000 ng/mL. This suggests that zaleplon disposition should not be sensitive to alterations in protein binding. The blood to plasma ratio for zaleplon is approximately 1, indicating that zaleplon is uniformly distributed throughout the blood with no extensive distribution into red blood cells.

Metabolism

After oral administration, zaleplon is extensively metabolized, with less than 1% of the dose excreted unchanged in urine. Zaleplon is primarily metabolized by aldehyde oxidase to form 5-oxo-zaleplon. Zaleplon is metabolized to a lesser extent by cytochrome P450 (CYP) 3A4 to form desethylzaleplon, which is quickly converted, presumably by aldehyde oxidase, to 5-oxo-desethylzaleplon. These oxidative metabolites are then converted to glucuronides and eliminated in urine. All of zaleplon’s metabolites are pharmacologically inactive.

Elimination

After either oral or IV administration, zaleplon is rapidly eliminated with a mean t½ of approximately 1 hour. The oral-dose plasma clearance of zaleplon is about 3 L/h/kg and the IV zaleplon plasma clearance is approximately 1 L/h/kg. Assuming normal hepatic blood flow and negligible renal clearance of zaleplon, the estimated hepatic extraction ratio of zaleplon is approximately 0.7, indicating that zaleplon is subject to high first-pass metabolism.

Effect of Food

In healthy adults a high-fat/heavy meal prolonged the absorption of zaleplon compared to the fasted state, delaying tmax by approximately 2 hours and reducing Cmax by approximately 35%. Zaleplon AUC and elimination half-life were not significantly affected. These results suggest that the effects of zaleplon on sleep onset may be reduced if it is taken with or immediately after a high-fat/heavy meal.

Special Populations

Age

The pharmacokinetics of zaleplon have been investigated in three studies with elderly men and women ranging in age from 65 to 85 years. The pharmacokinetics of zaleplon in elderly subjects, including those over 75 years of age, are not significantly different from those in young healthy subjects.

Gender

There is no significant difference in the pharmacokinetics of zaleplon in men and women.

Race

The pharmacokinetics of zaleplon have been studied in Japanese subjects as representative of Asian populations. For this group, Cmax and AUC were increased 37% and 64%, respectively. This finding can likely be attributed to differences in body weight, or alternatively, may represent differences in enzyme activities resulting from differences in diet, environment, or other factors. The effects of race on pharmacokinetic characteristics in other ethnic groups have not been well characterized.

Hepatic impairment

Zaleplon is metabolized primarily by the liver and undergoes significant presystemic metabolism. Consequently, the oral clearance of zaleplon was reduced by 70% and 87% in compensated and decompensated cirrhotic patients, respectively, leading to marked increases in mean Cmax and AUC (up to 4-fold and 7-fold in compensated and decompensated patients, respectively), in comparison with healthy subjects. The dose of zaleplon should therefore be reduced in patients with mild to moderate hepatic impairment (see DOSAGE AND ADMINISTRATION). Zaleplon is not recommended for use in patients with severe hepatic impairment.

Renal impairment

Drug-Drug Interactions

Because zaleplon is primarily metabolized by aldehyde oxidase, and to a lesser extent by CYP3A4, inhibitors of these enzymes might be expected to decrease zaleplon’s clearance and inducers of these enzymes might be expected to increase its clearance. Zaleplon has been shown to have minimal effects on the kinetics of warfarin (both R- and S- forms), imipramine, ethanol, ibuprofen, diphenhydramine, thioridazine, and digoxin. However, the effects of zaleplon on inhibition of enzymes involved in the metabolism of other drugs have not been studied. (See Drug Interactions under PRECAUTIONS.)

Clinical Trials

Controlled Trials Supporting Effectiveness

Zaleplon (typically administered in doses of 5 mg, 10 mg, or 20 mg) has been studied in patients with chronic insomnia (n = 3,435) in 12 placebo- and active-drug-controlled trials. Three of the trials were in elderly patients (n = 1,019). It has also been studied in transient insomnia (n = 264). Because of its very short half­-life, studies focused on decreasing sleep latency, with less attention to duration of sleep and number of awakenings, for which consistent differences from placebo were not demonstrated. Studies were also carried out to examine the time course of effects on memory and psychomotor function, and to examine withdrawal phenomena.

Transient Insomnia

Normal adults experiencing transient insomnia during the first night in a sleep laboratory were evaluated in a double-blind, parallel-group trial comparing the effects of two doses of zaleplon (5 mg and 10 mg) with placebo. Zaleplon 10 mg, but not 5 mg, was superior to placebo in decreasing latency to persistent sleep (LPS), a polysomnographic measure of time to onset of sleep.

Chronic Insomnia

Non-elderly patients

Adult outpatients with chronic insomnia were evaluated in three double-blind, parallel-group outpatient studies, one of 2 weeks duration and two of 4 weeks duration, that compared the effects of zaleplon at doses of 5 mg (in two studies), 10 mg, and 20 mg with placebo on a subjective measure of time to sleep onset (TSO). Zaleplon 10 mg and 20 mg were consistently superior to placebo for TSO, generally for the full duration of all three studies. Although both doses were effective, the effect was greater and more consistent for the 20 mg dose. The 5 mg dose was less consistently effective than were the 10 mg and 20 mg doses. Sleep latency with zaleplon 10 mg and 20 mg was on the order of 10 to 20 minutes (15% to 30%) less than with placebo in these studies.

Adult outpatients with chronic insomnia were evaluated in six double-blind, parallel-group sleep laboratory studies that varied in duration from a single night up to 35 nights. Overall, these studies demonstrated a superiority of zaleplon 10 mg and 20 mg over placebo in reducing LPS on the first 2 nights of treatment. At later time points in 5-, 14-, and 28-night studies, a reduction in LPS from baseline was observed for all treatment groups, including the placebo group, and thus, a significant difference between zaleplon and placebo was not seen beyond 2 nights. In a 35-night study, zaleplon 10 mg was significantly more effective than placebo in reducing LPS at the primary efficacy endpoint on nights 29 and 30.

Elderly patients

Elderly outpatients with chronic insomnia were evaluated in two 2-week, double-blind, parallel-group outpatient studies that compared the effects of zaleplon 5 mg and 10 mg with placebo on a subjective measure of time to sleep onset (TSO). Zaleplon at both doses was superior to placebo on TSO, generally for the full duration of both studies, with an effect size generally similar to that seen in younger persons. The 10 mg dose tended to have a greater effect in reducing TSO.

Elderly outpatients with chronic insomnia were also evaluated in a 2-night sleep laboratory study involving doses of 5 mg and 10 mg. Both 5 mg and 10 mg doses of zaleplon were superior to placebo in reducing latency to persistent sleep (LPS).

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