Zaleplon

Zaleplon is a pyrazolopyrimidine hypnotic that is structurally different from benzodiazepines and other hypnotics. Zaleplon binds selectively to the benzodiazepine type I receptor.

Zaleplon’s pharmacokinetic profile shows rapid absorption and elimination. In combination with its subtype selective receptor-binding characteristics, with high selectivity and low affinity for the benzodiazepine type I receptor, these properties are responsible for the overall characteristics of zaleplon.

Zaleplon’s efficacy has been demonstrated in both sleep laboratory studies using objective polysomnography (PSG) measures of sleep and in outpatient studies using patient questionnaires to assess sleep. In these studies, patients were diagnosed with primary (psychophysiological) insomnia.

Absorption

Zaleplon is rapidly and almost completely absorbed after oral administration, and peak concentrations are reached in approximately 1 hour. At least 71% of the orally-administered dose is absorbed. Zaleplon undergoes presystemic metabolism, resulting in an absolute bioavailability of approximately 30%.

Distribution

Zaleplon is lipophilic with a volume of distribution of about 1.4 ± 0.3 l/kg following intravenous administration. The in vitro plasma protein binding is approximately 60%, suggesting little risk of active substance interaction due to protein binding.

Metabolism

Zaleplon is primarily metabolised by aldehyde oxidase to form 5-oxo-zaleplon. Additionally, zaleplon is metabolised by CYP3A4 to form desethylzaleplon which is further metabolised by aldehyde oxidase to form 5-oxo-desethylzaleplon. The oxidative metabolites are further metabolised by conjugation via glucuronidation. All of zaleplon’s metabolites are inactive in both animal behavioural models and in vitro activity assays.

Zaleplon plasma concentrations increased linearly with dose, and zaleplon showed no signs of accumulation following administration of up to 30 mg/day. The elimination half-life of zaleplon is approximately 1 hour.

Excretion

Zaleplon is excreted in the form of inactive metabolites, mainly in the urine (71%) and faeces (17%). Fifty-seven percent (57%) of the dose is recovered in urine in the form of 5-oxo-zaleplon and its glucuronide metabolite, an additional 9% is recovered as 5-oxo-desethylzaleplon and its glucuronide metabolite. The remainder of the urinary recovery consists of minor metabolites. The majority of the faecal recovery consists of 5-oxo-zaleplon.

Hepatic Impairment

Zaleplon is metabolised 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 C_max and AUC (up to 4-fold and 7-fold in compensated and decompensated patients, respectively) relative to healthy subjects. The dose of zaleplon should be reduced in patients with mild to moderate hepatic impairment, and zaleplon is not recommended for use in patients with severe hepatic impairment.

Renal Impairment

The single dose pharmacokinetics of zaleplon were studied in patients with mild (creatinine clearance 40 to 89 ml/min) and moderate (20 to 39 ml/min) renal impairment, and in patients on dialysis. In patients with moderate impairment and those on dialysis there was a reduction of approximately 23% in peak plasma concentration compared to healthy volunteers. The extent of exposure to zaleplon was similar among all groups. Therefore, no dose adjustment is necessary in patients with mild to moderate renal impairment. Zaleplon has not been adequately studied in patients with severe renal impairment.

Repeated dose toxicity

In line with effects observed with other compounds binding to benzodiazepine receptors, reversible increases in liver and adrenal weights in rats and dogs were only noted upon repeated oral administration of high multiples of the maximum human therapeutic dose. At these doses, a significant reduction in the weight of both prostate and testes was apparent in a three month study in prepubescent dogs.

Reproduction toxicity

In a fertility and reproductive performance study in rats, mortality and decreased fertility were observed in males and females at an oral zaleplon dose of 100 mg/kg/day (equivalent to 49-times the maximum recommended human dose (MRHD) of 20 mg on a mg/m² basis). Follow-up studies indicated that impaired fertility was due to an effect on the female.

In embryofetal development studies, oral administration of zaleplon up to 100 mg/kg/day and 50 mg/kg/day to pregnant rats and rabbits, respectively, produced no evidence of teratogenicity (equivalent to 49- (rat) and 48-(rabbit) times the MRHD on a mg/m² basis). Pre-and postnatal growth of rats was reduced at the maternally toxic dose of 100 mg/kg/day. The no-effect dose for growth of rat offspring was 10 mg/kg (equivalent to 5-times the MRHD on a mg/m² basis). No adverse effects on embryofetal development were observed in rabbits.

In a pre- and postnatal development study in rats, increased stillbirth and postnatal mortality, and decreased growth and physical development, were observed in the offspring of females treated with doses of ≥7 mg/kg/day that did not elicit maternal toxicity. The no-effect dose for postnatal development was 1 mg/kg/day (equivalent to 0.5-times the MRHD on a mg/m² basis). In a subsequent cross-fostering study, adverse effects on offspring viability and growth appeared to result from both in utero and lactational exposure to zaleplon.

Carcinogenicity

Oral administration of zaleplon to rats for 104 consecutive weeks at dosage levels up to 20 mg/kg/day did not result in compound-related tumorigenicity. Oral administration of zaleplon to mice for 65 or 104 consecutive weeks at high dosage levels (≥100 mg/kg/day) elicited a statistically significant increase in benign but not in malignant liver tumors. The increased incidence of benign liver tumors in mice was likely an adaptive event.

Overall, the results of the preclinical studies do not suggest any significant safety hazard for use of zaleplon at recommended doses in humans.