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The Pharmacokinetics of Sodium Oxybate Oral Solution following Acute and Chronic Administration to Narcoleptic Patients

From Orphan Medical, Inc., Minnetonka, Minnesota (Dr. Borgen); Okerholm & Associates, Inc., Palm City, Florida (Dr. Okerholm); CPKD Solutions, Inc., Research Triangle Park, North Carolina (Dr. Lai); and Tri-State Sleep Disorders Center, Cincinnati, Ohio (Dr. Scharf). Dr. Borgen and Dr. Okerholm are fellows of the American College of Clinical Pharmacology.

This trial was conducted to evaluate the pharmacokinetics and safety of a sodium oxybate (gamma-hydroxybutyrate [GHB]) oral solution in narcoleptic patients after acute and chronic treatment. An open-label, two-period, two-treatment study design was used. Trial subjects included 13 patients with polysomnographically confirmed narcolepsy. The patients were administered a bedtime dose of 4.5 g of sodium oxybate while in a sleep research center. They were subsequently treated with sodium oxybate at the nightly dose of 4.5 g for 8 weeks. The patients then returned to the sleep center and were again treated with the 4.5-g sodium oxybate dose at bedtime. Blood samples (5 mL) were collected at 18 time points before and up to 7 hours after both the first dose of sodium oxybate and following 8 weeks of dosing. Plasma samples were analyzed for oxybate content by a validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. Noncompartmental methods were applied in the determination of pharmacokinetic parameters from each patient's plasma oxybate concentration versus time curve. No serious adverse events were recorded, and all patients completed the study. Headache, enuresis, and leg cramps were reported as adverse experiences. With both acute and chronic dosing, sodium oxybate was rapidly absorbed and eliminated with an apparent half-life of about 40 minutes. The only changes observed in the kinetics of oxybate after 8 weeks of treatment were a 13% and 16% increase in peak concentration (C_max) and systemic exposure (AUC), respectively. The pharmacokinetics of sodium oxybate in narcoleptic patients were not changed in any clinically significant manner when the drug was chronically administered. The drug was well tolerated.

Key Words: Sodium oxybate • gamma hydroxybutyrate • narcolepsy • pharmacokinetics

Address for reprints: Lowell A. Borgen, PhD, Orphan Medical, Inc., 13911 Ridgedale Drive, Suite 250, Minnetonka, MN 55305.

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