-subject variability of esketamine ranges from 27% to 66% for Cmax and 18% to 45%for AUC∞. The intra-subject variability of esketamine is approximately 15% for Cmax and 10%for AUC∞.
Distribution
The mean steady-state volume of distribution of esketamine administered by the intravenousroute is 709 L.
Protein binding of esketamine was approximately 43% to 45%.
The brain-to-plasma ratio of noresketamine is 4- to 6-times lower than that of esketamine.
Elimination
After Cmax was reached following intranasal administration, the decline in plasma esketamineconcentrations was biphasic, with rapid decline for the initial 2 to 4 hours and a mean terminalhalf-life (t1/2) that ranged from 7 to 12 hours. The mean clearance of esketamine is approximately89 L/hour following intravenous administration. The elimination of the major metabolite,noresketamine, from plasma is slower than esketamine. The decline of noresketamine plasmaconcentrations is biphasic, with rapid decline for the initial 4 hours and a mean terminal t1/2 ofapproximately 8 hours.
Metabolism
Esketamine is primarily metabolized to noresketamine metabolite via cytochrome P450 (CYP)enzymes CYP2B6 and CYP3A4 and to a lesser extent CYP2C9 and CYP2C19. Noresketamine ismetabolized via CYP-dependent pathways and certain subsequent metabolites undergoglucuronidation.
Excretion
Less than 1% of a dose of nasal esketamine is excreted as unchanged drug in urine. Followingintravenous or oral administration, esketamine-derived metabolites were primarily recovered inurine (≥ 78% of a radiolabeled dose) and to a lesser extent in feces (≤ 2% of a radiolabeled dose).
Specific Populations
Exposures of esketamine in specific populations are summarized in Figure 1. No significantdifferences in the pharmacokinetics of SPRAVATO nasal spray were observed for sex and totalbody weight (>39 to 170 kg) based on population PK analysis. There is no clinical experiencewith SPRAVATO nasal spray in patients on renal dialysis or with severe (Child-Pugh class C)hepatic impairment.
Figure 1: Effect of Specific Populations on the Pharmacokinetics of EsketamineDrug Interaction StudiesThe effect of other drugs on the exposures of intranasally administered esketamine aresummarized in Figure 2. The effect of SPRAVATO on the exposures of other drugs aresummarized in Figure 3. Based on these results, none of the drug-drug interactions are clinicallysignificant
Figure 2: Effect of Co-administered Drugs on the Pharmacokinetics of Esketamine
Figure 3: Effect of Esketamine on the Pharmacokinetics of Co-Administered Drugs
In Vitro Studies
Enzyme Systems: Esketamine has modest induction effects on CYP2B6 and CYP3A4 in humanhepatocytes. Esketamine and its major metabolites do not induce CYP1A2. Esketamine and itsmajor circulating metabolites did not show inhibition potential against CYPs and UGTs, exceptfor a weak reversible inhibition of noresketamine on CYP3A4.
Transporter Systems: Esketamine is not a substrate of transporters P-glycoprotein (P-gp;multidrug resistance protein 1), breast cancer resistance protein (BCRP), or organic aniontransporter (OATP) 1B1, or OATP1B3. Esketamine and its major circulating metabolites do notinhibit these transporters or multi-drug and toxin extrusion 1 (MATE1) and MATE2-K, ororganic cation transporter 2 (OCT2), OAT1, or OAT3.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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