What are the pharmacokinetics of Lunesta (eszopiclone) in adult patients, particularly those with a history of sleep disorders or potential underlying medical conditions?

Pharmacokinetics of Lunesta (Eszopiclone)

Absorption

Eszopiclone is rapidly absorbed after oral administration, reaching peak plasma concentrations (Cmax) approximately 1 hour after dosing, with a bioavailability of approximately 80%. 1, 2

• The time to peak concentration (tmax) ranges from 1.0 to 1.6 hours following a 3 mg dose 1, 2
• Administration with a high-fat meal reduces Cmax by 21% and delays tmax by approximately 1 hour, though total drug exposure (AUC) remains unchanged 1
• Taking eszopiclone with or immediately after a high-fat/heavy meal may reduce effects on sleep onset 1

Distribution

• Eszopiclone is weakly bound to plasma proteins (52-59%), resulting in a large free fraction that minimizes the risk of drug-drug interactions caused by protein binding 1
• The blood-to-plasma ratio is less than one, indicating no selective uptake by red blood cells 1
• The drug is extensively distributed to body tissues including the brain 2

Metabolism

Eszopiclone undergoes extensive hepatic metabolism primarily via CYP3A4 and CYP2E1 enzymes through oxidation and demethylation pathways. 1

• The primary plasma metabolites are (S)-zopiclone-N-oxide and (S)-N-desmethyl zopiclone 1
• The N-desmethyl metabolite binds to GABA receptors with substantially lower potency than the parent compound, while the N-oxide metabolite shows no significant GABA receptor binding 1
• Eszopiclone does not inhibit CYP450 enzymes (1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4), minimizing potential for drug-drug interactions 1

Elimination

The terminal elimination half-life (t1/2) is approximately 6 hours in healthy adults, allowing for effective sleep maintenance without significant next-day residual effects. 1, 2

• Up to 75% of an oral dose is excreted in urine, primarily as metabolites 1
• Less than 10% of the administered dose is excreted unchanged in urine 1
• The pharmacokinetic profile is dose-proportional over the range of 1 to 6 mg 1
• Eszopiclone does not accumulate with once-daily administration 1

Special Population Pharmacokinetics

Elderly Patients (≥65 years)

Elderly patients experience a 41% increase in total drug exposure (AUC) and prolonged elimination half-life of approximately 9 hours compared to younger adults. 1, 2

• Cmax remains unchanged in elderly patients 1
• The maximum recommended dose for elderly patients is 2 mg due to increased drug exposure 3, 1

Hepatic Impairment

Patients with severe hepatic impairment have a 2-fold increase in eszopiclone exposure compared to healthy volunteers. 1

• Cmax and tmax remain unchanged regardless of hepatic function 1
• No dose adjustment is necessary for mild-to-moderate hepatic impairment 1
• Dose reduction to a maximum of 2 mg is recommended for severe hepatic impairment 3, 1

Renal Impairment

• The pharmacokinetic profile is not substantially modified in patients with renal failure 2
• No dosage adjustment is required for patients with renal dysfunction 4

Gender and Race

• Pharmacokinetics are similar between men and women 1
• Pharmacokinetic profiles appear similar across all races studied 1

Clinical Implications

The 6-hour half-life provides effective sleep maintenance throughout the night while minimizing morning residual sedation. 1, 2

• The rapid absorption (1-hour tmax) facilitates quick sleep onset when taken immediately before bedtime 1, 2
• The lack of drug accumulation with nightly dosing supports long-term use without dose escalation 1
• Patients should ensure at least 7-8 hours are available for sleep before planned awakening 3