Mechanism of Action

The precise mechanism by which sodium oxybate produces an effect on cataplexy is unknown.

Sodium oxybate is rapidly but incompletely absorbed after oral administration; absorption is delayed and decreased by a high fat meal. It is eliminated mainly by metabolism with a half-life of 0.5 to 1 hour. Pharmacokinetics are nonlinear with blood levels increasing 3.7-fold as dose is doubled from 4.5 to 9 grams (g). The pharmacokinetics are not altered with repeat dosing.

Sodium oxybate is absorbed rapidly following oral administration with an absolute bioavailability of about 25%. The average peak plasma concentrations (1^st and 2^nd peak) following administration of a 9 g daily dose divided into two equivalent doses given four hours apart were 78 and 142 micrograms/milliliter (mcg/mL), respectively. The average time to peak plasma concentration (T_max) ranged from 0.5 to 1.25 hours in eight pharmacokinetic studies.

Following oral administration, the plasma levels of sodium oxybate increase more than proportionally with increasing dose. Single doses greater than 4.5 g have not been studied. Administration of sodium oxybate immediately after a high fat meal resulted in delayed absorption (average T_max increased from 0.75 hr to 2.0 hr) and a reduction in peak plasma level (C_max) by a mean of 58% and of systemic exposure (AUC) by 37%.

Sodium oxybate is a hydrophilic compound with an apparent volume of distribution averaging 190-384 mL/kg. At sodium oxybate concentrations ranging from 3 to 300 mcg/mL, less than 1% is bound to plasma proteins.

Animal studies indicate that metabolism is the major elimination pathway for sodium oxybate, producing carbon dioxide and water via the tricarboxylic acid (Krebs) cycle and secondarily by beta-oxidation. The primary pathway involves a cytosolic NADP⁺-linked enzyme, GHB dehydrogenase, that catalyses the conversion of sodium oxybate to succinic semialdehyde, which is then biotransformed to succinic acid by the enzyme succinic semialdehyde dehydrogenase. Succinic acid enters the Krebs cycle where it is metabolized to carbon dioxide and water. A second mitochondrial oxidoreductase enzyme, a transhydrogenase, also catalyses the conversion to succinic semialdehyde in the presence of a-ketoglutarate. An alternate pathway of biotransformation involves b-oxidation via 3,4-dihydroxybutyrate to carbon dioxide and water. No active metabolites have been identified.

Studies in vitro with pooled human liver microsomes indicate that sodium oxybate does not significantly inhibit the activities of the human isoenzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A up to the concentration of 3 mM (378 mcg/mL). These levels are considerably higher than levels achieved with therapeutic doses.

The clearance of sodium oxybate is almost entirely by biotransformation to carbon dioxide, which is then eliminated by expiration. On average, less than 5% of unchanged drug appears in human urine within 6 to 8 hours after dosing. Fecal excretion is negligible.

The pharmacokinetics of sodium oxybate in patients greater than the age of 65 years have not been studied.

The pharmacokinetics of sodium oxybate in patients under the age of 18 years have not been studied.

In a study of 18 female and 18 male healthy adult volunteers, no gender differences were detected in the pharmacokinetics of sodium oxybate following a single oral dose of 4.5 g.

Brand Name: Xyrem
Generic Name: Sodium Oxybate

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