Drug Interactions between darunavir and eszopiclone

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of both zopiclone and its pharmacologically active S(-) enantiomer, eszopiclone. Zopiclone has been shown in vitro to be metabolized by CYP450 3A4 and CYP450 2C8, while eszopiclone is primarily metabolized by CYP450 3A4 and 2E1 via demethylation and oxidation. In 18 healthy subjects, administration of a single 3 mg dose of eszopiclone with the potent CYP450 3A4 inhibitor ketoconazole (400 mg daily for 5 days) increased eszopiclone half-life, peak plasma concentration (Cmax) and systemic exposure (AUC) by 1.3-, 1.4- and 2.2-fold, respectively. In 10 healthy young subjects, itraconazole 200 mg daily given for 4 days increased the Cmax and AUC of a single 7.5 mg dose of zopiclone by 29% and 73%, respectively, and prolonged its half-life by 40%. A case report describes an 86-year-old woman who experienced morning drowsiness during coadministration of zopiclone and nefazodone, a known potent CYP450 3A4 inhibitor. Zopiclone plasma concentrations were measured both during and after withdrawal of nefazodone therapy. Following discontinuation of nefazodone due to lack of therapeutic effect, the plasma concentration of S(-) zopiclone decreased from 107 to 16.9 ng/mL, and that of R(+) zopiclone decreased from 20.6 to 1.45 ng/mL. Limited data are available regarding use with moderate CYP450 3A4 inhibitors. When 10 healthy young volunteers were given a single 7.5 mg dose of zopiclone on the 6th day of treatment with 500 mg erythromycin base three times daily, mean half-life, Cmax and AUC of zopiclone increased by approximately 42%, 38% and 77%, respectively, compared to administration with placebo. Plasma zopiclone concentration increased nearly 4-fold at 0.5 hour postdose and 2-fold at 1 hour postdose, and time to reach peak plasma concentration (Tmax) decreased from 2 hours to 1 hour, suggesting accelerated absorption due to increased gastric emptying induced by erythromycin.

MANAGEMENT: Caution is advised when zopiclone or eszopiclone is coadministered with moderate CYP450 3A4 inhibitors. A dosage reduction may be required if an interaction is suspected. Patients should be advised to avoid driving or operating hazardous machinery until they know how these medications affect them, preferably at least 12 hours after administration of the hypnotic.

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