Chemical formula: C₂₂H₁₇ClF₃N₉O₂ PubChem compound: 162533924
Ensitrelvir selectively inhibits SARS-CoV-2 3C-like (3CL) protease, an essential enzyme for the processing of the polyprotein encoded by the SARS-CoV-2 gene, which thereby inhibits SARS-CoV-2 replication. The 50% inhibitory concentration (IC50) of ensitrelvir for SARS-CoV-2 3CL protease activity was 0.0132 μmol/L.
No QTc prolongation was observed at the plasma concentration range of ensitrelvir by using concentration-QTc analysis based on the data after single doses of ensitrelvir 20 to 2000 mg.
Following oral administration of ensitrelvir once daily with a loading dose of 375 mg on Day 1 and a maintenance dose of 125 mg on Days 2 to 5, the geometric mean (CV%) ensitrelvir Cmax and AUC0-τ on Day 1 were 19.7 (21.1%) μg/mL and 325.0 (15.7%) μg·hr/mL, respectively, and those on Day 5 were 24.8 (13.4%) μg/mL and 475.5 (15.0%) μg·hr/mL, respectively. The median time to Cmax (Tmax) is 2.75 to 3.25 hours. The absolute bioavailability of ensitrelvir has not been established.
In healthy adults who received single oral administration of ensitrelvir 375 mg in the fed state (after a high fat high caloric breakfast), the AUC increased by approximately 25% and the median Tmax was delayed from 2.50 hours (in the fasted state) to 6.00 hours (in the fed state), but did not influence the Cmax of ensitrelvir. There was no clinically meaningful difference in the exposure of ensitrelvir between the fasted and fed states, although Tmax is delayed in the fed state compared to the fasted state.
The human serum protein binding ratio is 97.7% to 98.7%.
The geometric mean apparent volume of distribution in the terminal elimination phase was from 13.5 to 20.6 L after single oral administration of ensitrelvir (suspension) 20 to 2000 mg in the fasted state to Japanese healthy adult male participants.
An in vitro study revealed that multiple CYP enzymes including CYP3A contributed to form ensitrelvir triazole N-desmethyl.
When ensitrelvir was orally administered with a single dose in the fasted state for healthy adults, mainly unchanged ensitrelvir was detected in plasma and chlorinated metabolite of ensitrelvir was detected as a metabolite in plasma. Minor metabolites were observed in the urine (ensitrelvir triazole N-desmethyl, ensitrelvir indazole N-desmethyl, and an unknown metabolite1) and faeces (N-deindazolated form of ensitrelvir, ensitrelvir triazole N-desmethyl, ensitrelvir indazole N-desmethyl, ensitrelvir 3-indazolinone, ensitrelvir indazole 4-Cl, and another unknown metabolite 2).
The majority of elimination of ensitrelvir is via the biliary route with some contribution from renal elimination. Following [14C]-ensitrelvir (suspension) was administered orally at a dose of 375 mg to healthy participants, approximately 65% and 26% of ensitrelvir was recovered in faeces and urine. Unchanged ensitrelvir was mainly detected in the plasma, which was approximately 90% of the total radioactivity in the plasma.
Following oral administration of ensitrelvir once daily with a loading dose of 375 mg on Day 1 and a maintenance dose of 125 mg on Days 2 to 5, the geometric mean terminal elimination half-life on Day 5 was 58 hours.
Ensitrelvir exhibited almost linear pharmacokinetics in the fasted state within the dose range of 20 mg to 2000 mg (suspension) in healthy adult volunteers.
In a population pharmacokinetic analysis, no clinically significant differences in the pharmacokinetics of ensitrelvir were observed based on age (12 to 91 years of age), gender, or race/ethnicity.
The exposure in elderly participants aged ≥65 years of age was comparable to that in healthy adult participants.
There was a trend towards higher exposure for lower body weight, but this was not considered clinically relevant.
Pharmacokinetic studies have not been performed with ensitrelvir in infants and children under 12 years of age.
The adolescents who received ensitrelvir ranged in weight from 32 kg to 112 kg. Pharmacokinetic analyses confirmed ensitrelvir exposures in adolescents were comparable to those of adults.
Pharmacokinetic studies have been performed with ensitrelvir in patients with renal impairment. Compared to healthy controls with no renal impairment, the Cmax and AUCinf of ensitrelvir increased by 1.32- and 1.44-fold in patients with mild renal impairment, 1.33- and 1.49-fold in patients with moderate renal impairment, and 1.11- and 1.60-fold in patients with severe renal impairment, respectively.
Renal impairment does not have a clinically meaningful effect on the pharmacokinetics of ensitrelvir.
Pharmacokinetic studies have been performed with ensitrelvir in patients with mild to moderate hepatic impairment.
Compared to healthy controls with no hepatic impairment, the Cmax and AUCinf of ensitrelvir was 0.89-, and 1.03-fold in patients with mild hepatic impairment, 0.74- and 0.87-fold in patients with moderate hepatic impairment, respectively. Therefore, mild and moderate hepatic impairment does not have a clinically meaningful effect on the pharmacokinetics of ensitrelvir.
Pharmacokinetic studies have not been performed with ensitrelvir in patients with severe hepatic impairment.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
Based on the results of non-clinical general toxicity studies, the adverse effects of ensitrelvir include decreased food consumption, decreased erythrocyte parameters, inflammatory changes in multiple organs, decreased platelet count and vomiting. The findings are observed at 2 to 3-fold higher exposure than the clinical exposure dose. In the 2 and 4 week oral toxicity study in monkeys, infiltration by inflammatory cells, mainly mononuclear cells, was observed in the hepatic portal vein, gallbladder, lung/bronchus at a dose equivalent to 8.0 times or more than the clinical exposure dose.
No carcinogenicity studies have been conducted with ensitrelvir.
Ensitrelvir did not affect male and female fertility and early embryo development in rats at doses up to a dose equivalent 8.2 to 10 times the clinical exposure dose.
In an embryo-foetal development study in rats, ensitrelvir did not induce malformations or embryo-foetal lethality up to a dose equivalent 6.6 times the clinical exposure dose. However, low food consumption and body weight in dams and slight foetal growth retardation and high frequency of short supernumerary rib were noted at 1000 mg/kg/day a dose equivalent 6.6 times the clinical exposure dose.
In an embryo-foetal development study in rabbits, ensitrelvir induced embyo-foetal lethality or malformation with severe maternal toxicity by continuous administration at doses equivalent to 5.0 and 7.4 times the clinical exposure dose, respectively during rabbit organogenesis. The changes noted at doses equivalent to 5.0 and 7.4 times the clinical exposure dose, respectively, were malformations of the axial skeleton, the changes associated with vertebral malformations such as skeletal variations of the thoracic centrum, and short tail, and high frequencies of full supernumerary rib and/or supernumerary lumbar vertebra as skeletal variation. In addition, abortion associated with maternal toxicity was observed in 1 dam at doses equivalent to 5.0 times the clinical exposure dose.
In a pre-and postnatal developmental and maternal function study in rats a decrease in survival rate on postnatal day 4 and growth retardation were observed in the pups at a dose equivalent 6.6 times the clinical exposure dose.
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