Chemical formula: C₂₃H₂₁F₇N₄O₃ Molecular mass: 534.427 g/mol PubChem compound: 135413536
Aprepitant is a selective high-affinity antagonist at human substance P neurokinin 1 (NK1) receptors.
Aprepitant displays non-linear pharmacokinetics. Both clearance and absolute bioavailability decrease with increasing dose.
The mean absolute oral bioavailability of aprepitant is 67% for the 80 mg capsule and 59% for the 125 mg capsule. The mean peak plasma concentration (Cmax) of aprepitant occurred at approximately 4 hours (tmax). Oral administration of the capsule with an approximately 800 Kcal standard breakfast resulted in an up to 40% increase in AUC of aprepitant. This increase is not considered clinically relevant.
The pharmacokinetics of aprepitant is non-linear across the clinical dose range. In healthy young adults, the increase in AUC0-∞ was 26% greater than dose proportional between 80 mg and 125 mg single doses administered in the fed state.
Following oral administration of a single 125 mg dose of aprepitant on Day 1 and 80 mg once daily on Days 2 and 3, the AUC0-24hr (mean±SD) was 19.6 ± 2.5 μg·h/mL and 21.2 ± 6.3 μg·h/mL on Days 1 and 3, respectively. Cmax was 1.6 ± 0.36 μg/mL and 1.4 ± 0.22 μg/mL on Days 1 and 3, respectively.
Aprepitant is highly protein bound, with a mean of 97%. The geometric mean apparent volume of distribution at steady state (Vdss) is approximately 66 L in humans.
Aprepitant undergoes extensive metabolism. In healthy young adults, aprepitant accounts for approximately 19% of the radioactivity in plasma over 72 hours following a single intravenous administration 100-mg dose of [14C]-fosaprepitant, a prodrug for aprepitant, indicating a substantial presence of metabolites in the plasma. Twelve metabolites of aprepitant have been identified in human plasma. The metabolism of aprepitant occurs largely via oxidation at the morpholine ring and its side chains and the resultant metabolites were only weakly active. In vitro studies using human liver microsomes indicate that aprepitant is metabolised primarily by CYP3A4 and potentially with minor contribution by CYP1A2 and CYP2C19.
Aprepitant is not excreted unchanged in urine. Metabolites are excreted in urine and via biliary excretion in faeces. Following a single intravenously administered 100 mg dose of [14C]-fosaprepitant, a prodrug for aprepitant, to healthy subjects, 57% of the radioactivity was recovered in urine and 45% in faeces.
The plasma clearance of aprepitant is dose-dependent, decreasing with increased dose and ranged from approximately 60 to 72 mL/min in the therapeutic dose range. The terminal half-life ranged from approximately 9 to 13 hours.
Following oral administration of a single 125 mg dose of aprepitant on Day 1 and 80 mg once daily on Days 2 through 5, the AUC0-24hr of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly (≥65 years) relative to younger adults. The Cmax was 10% higher on Day 1 and 24% higher on Day 5 in elderly relative to younger adults. These differences are not considered clinically meaningful. No dose adjustment for aprepitant is necessary in elderly patients.
Following oral administration of a single 125 mg dose of aprepitant, the Cmax for aprepitant is 16% higher in females as compared with males. The half-life of aprepitant is 25% lower in females as compared with males and its tmax occurs at approximately the same time. These differences are not considered clinically meaningful. No dose adjustment for aprepitant is necessary based on gender.
Mild hepatic impairment (Child-Pugh class A) does not affect the pharmacokinetics of aprepitant to a clinically relevant extent. No dose adjustment is necessary for patients with mild hepatic impairment. Conclusions regarding the influence of moderate hepatic impairment (Child-Pugh class B) on aprepitant pharmacokinetics cannot be drawn from available data.
There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh class C).
A single 240 mg dose of aprepitant was administered to patients with severe renal impairment (CrCl<30 mL/min) and to patients with end stage renal disease (ESRD) requiring haemodialysis.
In patients with severe renal impairment, the AUC0-∞ of total aprepitant (unbound and protein bound) decreased by 21% and Cmax decreased by 32%, relative to healthy subjects. In patients with ESRD undergoing haemodialysis, the AUC0- of total aprepitant decreased by 42% and Cmax decreased by 32%. Due to modest decreases in protein binding of aprepitant in patients with renal disease, the AUC of pharmacologically active unbound aprepitant was not significantly affected in patients with renal impairment compared with healthy subjects. Haemodialysis conducted 4 or 48 hours after dosing had no significant effect on the pharmacokinetics of aprepitant; less than 0.2% of the dose was recovered in the dialysate.
No dose adjustment for aprepitant is necessary for patients with renal impairment or for patients with ESRD undergoing haemodialysis.
As part of a 3-day regimen, dosing of aprepitant capsules (125/80/80-mg) in adolescent patients (aged 12 through 17 years) achieved an AUC0-24hr above 17 µg•hr/mL on Day 1 with concentrations (Cmin) at the end of Days 2 and 3 above 0.4 µg/mL in a majority of patients. The median peak plasma concentration (Cmax) was approximately 1.3 µg/mL on Day 1, occurring at approximately 4 hours. As part of a 3-day regimen, dosing of aprepitant powder for oral suspension (3/2/2-mg/kg) in patients aged 6 months to less than12 years achieved an AUC0-24hr above 17 µg•hr/mL on Day 1 with concentrations (Cmin) at the end of Days 2 and 3 above 0.1 µg/mL in a majority of patients. The median peak plasma concentration (Cmax) was approximately 1.2 µg/mL on Day 1, occurring between 5 and 7 hours.
A population pharmacokinetic analysis of aprepitant in paediatric patients (aged 6 months through 17 years) suggests that gender and race have no clinically meaningful effect on the pharmacokinetics of aprepitant.
Using a highly specific NK1-receptor tracer, positron emission tomography (PET) studies in healthy young men have shown that aprepitant penetrates into the brain and occupies NK1 receptors in a doseand plasma-concentration-dependent manner. Aprepitant plasma concentrations achieved with the 3-day regimen of aprepitant in adults are predicted to provide greater than 95% occupancy of brain NK1 receptors.
Pre-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. It should be noted that systemic exposure in adult male rats was lower than the therapeutic exposure in humans at 40 mg. Consequently, no adequate assessment of potential effects on male fertility in rats can be made. However, in a 9 month study in dogs, no organ weight changes nor gross or histomorphologic findings were present in male reproductive organs at systemic exposures 35-fold above the therapeutic exposure in humans at 40 mg. Although no adverse effects were noted in reproduction studies when adult female animals were exposed 3.5-to 4-fold above the therapeutic exposure in humans at 40 mg, the potential effects on reproduction of alterations in neurokinin regulation are unknown.
In a juvenile toxicity study in rats treated from post natal day 10 to day 63 aprepitant led to an earlier vaginal opening in females from 250 mg/kg b.i.d. and to a delayed preputial separation in males, from 10 mg/kg b.i.d. There were no margins to clinically relevant exposure. There were no treatment-related effects on mating, fertility or embryonic/foetal survival, and no pathological changes in the reproductive organs. In a juvenile toxicity study in dogs treated from post natal day 14 to day 42, a decreased testicular weight and Leydig cell size were seen in the males at 6 mg/kg/day and increased uterine weight, hypertrophy of the uterus and cervix, and oedema of vaginal tissues were seen in females from 4 mg/kg/day. There were no margins to clinically relevant exposure of aprepitant. For short term treatment according to recommended dose regimen these findings are considered unlikely to be clinically relevant.
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