Summary

• Please note that this document does not contain any reference to the local prescribing information. For specific information on the pharmacokinetics (PK) of SPRAVATO, please refer to your local product information.
• Expected time to peak plasma concentration for esketamine (ESK) is 20-40 minutes after the last nasal spray of a treatment session, after which ESK plasma concentrations decline rapidly. The mean terminal half-life (t1/2) is 7-12 hours.¹
• No accumulation of ESK in the plasma occurred after repeated administration following twice-weekly intranasal administration or less frequently.¹
• ESK exposure increased with dose from 28 mg to 84 mg. The increase in maximum concentration (Cmax) and area under the concentration-time curve (AUC) values were nearly dose proportional between 56 and 84 mg but less than dose proportional between 28 and 56 mg and 28 and 84 mg.¹
• ESK is extensively metabolized by the cytochrome P450 enzymes (CYP), largely 3A4 and 2B6.¹
• The major metabolic pathway is N-demethylation of ESK to form noresketamine. Noresketamine is further metabolized by CYP-dependent pathways.¹
• A population PK model assessed the impact of race/ethnicity, particularly with Japanese patients, and body weight on ESK and noresketamine exposure. The study found that nasal absorption and elimination of ESK were explained by body weight and not ethnicity/race. However, the impact of these covariates on exposure were not expected to be clinically relevant, and therefore, dose adjustments were unnecessary.² 

clinical data

Perez-Ruixo et al (2021)¹ studied the population PK of ESK nasal spray and its metabolite, noresketamine, in healthy subjects and patients with treatment resistant depression (TRD). Plasma concentration data from 13 clinical trials of SPRAVATO were pooled for the analysis.

Study Design/Methods

• A total of 9784 and 9397 plasma concentrations of ESK and noresketamine were collected from 820 patients who received ESK by the intranasal (IN), intravenous (IV), and oral (PO) routes, including 256 (31.2%) healthy subjects from phase 1 studies and 564 (68.8%) patients with TRD enrolled in phase 2 and phase 3 studies who received twice-weekly IN administration of SPRAVATO with a dose range of 28 mg - 112 mg.
• Of the 820 patients receiving ESK, 594 (72.4%) were White, 112 (13.2%) were Asian (Japanese, n=72 and Asian/non-Japanese, n=40), 56 (6.8%) were Black, and 58 (7.1%) were Other (ie, Native Hawaiian, Pacific Islander, American Indian, or Alaskan native). Approximately 58% were female; the mean age and body weight were 45 years and 74 kg.
• An open, linear, 3-compartment disposition model for ESK and an open, linear, 2-compartment disposition model for noresketamine with a separate hepato-portal compartment (“first-pass model”) provided a description of the time courses of plasma concentrations and variability after ESK administration as a nasal spray, IV infusion, or PO solution.
• To characterize SPRAVATO after IN dosing, a nasal depot compartment (representing the nasal cavity) was incorporated into the model, and a joint analysis of IN, IV, and PO  PK data was conducted.

Results

• After IN administration of 28 mg of SPRAVATO, 54% of the dose is absorbed through the nasal cavity to plasma, and 46% of the dose is swallowed. For the subsequent 28 mg doses, the fraction of the dose absorbed through the nasal cavity is reduced by 38%. Therefore, 44%, 40%, and 38% of the dose is absorbed through the nasal cavity for the 56, 84, and 112 mg doses, respectively.
  • The fraction of the SPRAVATO dose absorbed through the nasal cavity was complete and fast, with a mean absorption time of 0.341 hour.
  • The gastrointestinal absorption of the swallowed dose of SPRAVATO was incomplete and relatively slower than the nasal absorption, with a mean absorption time of 2.02 hours.
  • Given that 64% of the PO ESK dose overcomes gastrointestinal degradation and reaches the hepato-portal system where the first-pass hepatic metabolism takes place before ESK becomes bioavailable in the systemic circulation. About 29% of the dose that reaches the hepatic compartment accesses directly to the central compartment and the remaining 71% undergoes first-pass metabolism.
  • The absolute bioavailability after IN administration, considering direct absorption through the nasal cavity and PO bioavailability, was 63%, 54%, 51%, and 50% for the 28, 56, 84, and 112 mg ESK doses, respectively.
• Estimated ESK typical volumes of the central, shallow, and deep peripheral compartment and corresponding interindividual variability (coefficient of variation [CV]%) were 192 L (27.5%), 143 L (49.3%), and 417 L, respectively.
• ESK volume at steady state was 752 L.
• Intrinsic clearance and hepatic extraction were 392 L/h and 0.71, respectively, giving an estimated typical plasma clearance of 114 L/h. The terminal half-life (t_1/2) of ESK was estimated to be 11 hours.
• In the hepatic compartment, approximately 71% of ESK was metabolized to noresketamine, and 29% was eliminated though other metabolic routes.
• For the apparent central and peripheral volumes of distribution, the typical PK parameters of noresketamine were estimated to be 70.0 and 115 L, respectively, and apparent inter-compartmental flow and apparent clearance were 26.1 and 38.0 L/h, respectively.
• Noresketamine volume at steady state was 185 L. Its t_1/2 was estimated to be 7.5h.
• ESK and noresketamine demonstrated linear elimination, time-independent PK, and no accumulation with twice-weekly dosing.
• Model-predicted exposure metrics are summarized in Table: Model-based Derived Exposure Metrics for Esketamine and Noresketamine at Different Doses by Race and Age.
  • For ESK, C_max for a typical Asian non-Japanese patient was similar to a typical Caucasian patient but the exposure was ~8% higher. The C_max and AUC_0-24h were both 1.32-fold higher for a typical Japanese patient compared with a Caucasian patient.
  • For noresketamine, C_max and AUC_0-24h for a typical Asian non-Japanese patient was 1.24-fold and 1.36-fold higher, respectively, compared with a typical Caucasian patient. The C_max and AUC_0-24h was 1.22-fold and 1.48-fold higher for a typical Japanese patient compared with a Caucasian patient.
  • The impact of age on hepatic flow, and thus exposure, was also simulated using a 70-year-old patient as a reference.

Covariate Analysis

• Compared to non-Asian patients, Asian patients had a 64.0% and a 19.4% decrease in ESK elimination rate constant and apparent clearance of noresketamine, respectively.
• Sex, age, body weight, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGT), albumin, total bilirubin, total protein, estimated glomerular filtration rate (eGFR), and disease state (healthy patients vs patients with TRD) had no impact on ESK and noresketamine PK parameters.

Sensitivity Analysis

• Compared to other races (non-Asian and Asian non-Japanese patients), Japanese patients had a 34% increase in fraction of the nasal dose absorbed in the nasal cavity (P<0.001).
• From age 60 years onwards, hepatic flow decreased at a rate of 21.9 L/h/10 years (P<0.001). Hepatic flow was on average 25% lower in patients aged ≥77 years compared to patients aged <60 years.
• Kurosawa et al (2023)² aimed to update the previous population PK model for ESK and noresketamine using the combined data from study TRD2005, a phase 2b study, and the studies included in the previous analysis to reassess the intrinsic and extrinsic factors on ESK and noresketamine exposures.

Study Design/Methods

• Study TRD2005 was a phase 2b, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy, safety, and tolerability of fixed doses of SPRAVATO nasal spray (28, 56, or 84 mg) in conjunction with an oral antidepressant in Japanese  patients with TRD.
• The analysis data set for the present study was created by integrating data from study TRD2005 and 13 clinical studies (see methods for Perez-Ruixo et al study summarized above).
• The data set for the present study comprised of 10,548 and 10,161 plasma concentrations of ESK and noresketamine, respectively, from 942 subjects including 194 Japanese subjects.
• The previous popPK structure and model were retained with parameters re-estimated. To assess the impact of race/ethnicity and body weight on ESK and noresketamine exposures, C_max and AUC_0-24h after an 84-mg single dose of SPRAVATO were computed using the individual post hoc estimated parameters from the updated final model.
• Results
• The model revealed that interindividual variabilities in the nasal absorption and unspecific elimination of ESK were explained by body weight and not by ethnicity/race.
• Exposures of ESK in the group with heavier body weight (>90 kg) were lower relative to the reference group (60–90 kg) and exposure in the group with lower body weight (<60 kg) were higher vs. the reference group. However, the 90% CI of the geometric mean ratio (GMR) for C_max and AUC_0-24h were within 0.8–1.25.
• For noresketamine, the exposures of Asian patients were predicted to be higher vs. that of non-Asian patients (GMR, 1.36 to 1.37); the reason is unclear, however, the metabolite is thought to contribute minimally to antidepressant activity.
• The impact of these covariates on ESK and noresketamine exposures were not expected to be clinically relevant, and therefore, dose adjustments based on the covariates are unnecessary.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 7 March 2025.