rcinogenesis
Once-daily intranasal administration of esketamine at doses equivalent to 4.5, 15, and45 mg/kg/day (based on a 200-gram rat) did not increase the incidence of tumors in a 2-year ratcarcinogenicity study. At the highest dose, the AUC exposure to esketamine was lower than thehuman exposure (AUC) at the maximum recommended human dose (MRHD) of 84 mg.
Once-daily subcutaneous administration of esketamine up to 75 mg/kg/day (reduced to40 mg/kg/day during week 17) did not increase the incidence of tumors in a 6-month study intransgenic (Tg.rasH2) mice.
Mutagenesis
Racemic ketamine was not mutagenic with or without metabolic activation in the Ames test, butwas positive in an in vitro mouse lymphoma test in the presence of metabolic activation.
Intraperitoneally-injected ketamine did not show genotoxic properties in an in vivo bone marrowmicronucleus test in mice.
Genotoxic effects with esketamine were seen in a screening in vitro micronucleus test in thepresence of metabolic activation. However, intravenously-administered esketamine was devoidof genotoxic properties in an in vivo Comet assay in rat liver cells.
Impairment of Fertility
Esketamine was administered intranasally to both male and female rats before mating,throughout the mating period, and up to day 7 of gestation at doses equivalent to 4.5, 15, and45 mg/kg/day (based on a 200-gram rat), which are approximately 0.05, 0.3, and 0.6-times themaximum recommended human dose (MRHD) of 84 mg/day based on mean AUC exposures,respectively. Estrous cycle irregularities were observed at the high dose of 45 mg/kg/day andincreased time to mate was observed at doses ≥ 15mg/kg/day without an overall effect onmating or fertility indices. The No Observed Adverse Effect Level (NOAEL) for mating andfertility is 45 mg/kg/day which is 0.6 times the esketamine exposures at MRHD of 84 mg/day.
13.2 Animal Toxicology and/or Pharmacology
Neurotoxicity
In a single-dose neuronal toxicity study where esketamine was administered intranasally to adultfemale rats, there were no findings of neuronal vacuolation in the brain up to an estimated doseequivalent of 45 mg/kg for a 200-gram rat with a safety margin of 1.8 and 4.5 times the clinicalexposures for AUC and Cmax, respectively, to the MRHD of 84 mg/day. In a second single doseneurotoxicity study conducted with intranasally administered esketamine to adult female rats,there were no findings of neuronal necrosis up to a dose equivalent of 270 mg/kg for a 200-gramrat which has a safety margin of 18-fold and 23-fold, respectively, to AUC and Cmax exposures at
the MRHD of 84 mg/day. Neuronal vacuolation was not examined in this study.In a single-dose neuronal toxicity study in adult rats, subcutaneously administered racemic
ketamine caused neuronal vacuolation in layer I of the retrosplenial cortex of the brain withoutneuronal necrosis at a dose of 60 mg/kg. The NOAEL for vacuolation in this study was
15 mg/kg. Estimating 50% of the exposure to be from esketamine, the NOAEL for neuronalvacuolation is 1.6-times and 4.5-times and the NOAEL for neuronal necrosis is 10-times and16-times exposures, respectively, for AUC and Cmax to the clinical exposure at the MRHD of84 mg/day. The relevance of these findings to humans is unknown.
14 CLINICAL STUDIES
14.1 Treatment Resistant Depression
Short-Term Study
SPRAVATO was eva luated in a randomized, placebo-controlled, double-blind, multicenter,short-term (4-week), Phase 3 study (Study 1; NCT02418585 |
