Pharmacokinetics, Tolerability, and Safety of Esmethadone in Subjects with Chronic Kidney Disease or Hepatic Impairment.

Background And Objectives: Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is a low potency N-methyl--aspartate (NMDA) receptor channel blocker that showed a rapid and sustained adjunctive antidepressant effects in patients with major depressive disorder with inadequate response to ongoing serotonergic antidepressant treatment. Previous studies indicated that esmethadone is partially excreted by the kidney (53.9% of the dose) and by the liver (39.1% of the dose).

Methods: Here we studied the pharmacokinetics and safety of esmethadone after a single oral dose of 25 mg in subjects with different stages of kidney and liver impairment.

Results: In subjects with a mild and moderate decrease in glomerular fraction rate (GFR), esmethadone C and AUC values did not differ compared with healthy subjects. In patients with severe renal impairment, the ratios of C and AUC values compared with healthy subjects were above 100% (138.22-176.85%) and, while modest, these increases reached statistical significance. In subjects with end stage renal disease (ESRD) undergoing intermittent hemodialysis (IHD), C and AUC values were not statistically different compared with healthy subjects. IHD did not modified plasma total esmethadone concentrations in blood exiting versus entering the dialyzer. Dose adjustment is not warranted in subjects with mild-to-moderate impaired renal function. Dose reduction may be considered for select patients with severe renal disfunction. In subjects with mild-or-moderate hepatic impairment, C and AUC were approximately 20-30% lower compared with healthy controls. The drug free fraction increased with the severity of hepatic impairment, from 5.4% in healthy controls to 8.3% in subjects with moderate hepatic impairment.

Conclusion: Mild and moderate hepatic impairment has a minimal to modest impact on exposure to total or unbound esmethadone and dose adjustments are not warranted in subjects with mild and moderate hepatic impairment. Administration of esmethadone was well tolerated in healthy adult subjects, in subjects with mild or moderate hepatic impairment, and in subjects with mild moderate or severe renal impairment, including patients with ESRF undergoing dialysis.