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

Abstract

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.

Lactate Inhibits Lipolysis in Fat Cells through Activation of an Orphan G-protein-coupled Receptor, GPR81

“…The assays were performed in triplicates for each data point. EC 50 (Fig. 3C), in L-lactatetreated cells, V5-GPR81 staining appeared at high intensity in intracellular organelles (Fig.…”

“…The results show that L-lactate stimulates GTP␥S binding with an EC 50 value of about 5 mM ( Fig. 2A and Table 1) in cells transfected with human GPR81 (but not in control cells or cells expressing the niacin receptors (GPR109a or GPR109b)) ( Fig.…”

Sodium Oxybate for Narcolepsy with Cataplexy: Systematic Review and Meta-Analysis

“…Fourteen full-text articles were retrieved and examined for relevance, and 6 RCTs fulfilled the inclusion criteria, 20-25 along with 5 companion reports (Figure 1). [25][26][27][28] Two articles were excluded at the full-text level of screening because they were not RCTs, 29,30 and one study was excluded because it did not report any relevant outcomes. 31 There was excellent agreement between reviewers at level 1 screening (κ = 0.92, 95% CI: 0.81 to 1.03), and lower agreement at level 2 screening, due to the small number of studies included at this level (κ = 0.46, 95% CI: −0.08 to 1.00).…”

Relative Abuse Liability of GHB in Humans: A Comparison of Psychomotor, Subjective, and Cognitive Effects of Supratherapeutic Doses of Triazolam, Pentobarbital, and GHB

“…GHB is used clinically for treatment of narcolepsy in the US (Xyrem; Fuller and Hornfeldt, 2003;Borgen et al, 2004) and for treatment of alcoholism in Europe (Alcover; Poldrugo and Addolorato, 1999;Beghè and Carpanini, 2000). Reports of GHB overdose (Caldicott et al, 2004;Kintz et al, 2005), withdrawal (Galloway et al, 1997), and drug-facilitated sexual assault (Schwartz et al, 2000;Varela et al, 2004) have appeared in the literature and are thought to be related to the recreational use of GHB, which has been reported in North America (Miotto et al, 2001;Romanelli et al, 2003;Barrett et al, 2005), Europe (Bellis et al, 2003;Gonzalez and Nutt, 2005;Liechti et al, 2006), and Australia (Degenhardt et al, 2005).…”