Chemical formula: C₂₅H₂₆F₆N₂O₂ Molecular mass: 500.485 g/mol PubChem compound: 10311306
Rolapitant is a selective antagonist of human substance P/neurokinin 1 (NK1) receptors.
Rolapitant displays linear PK with exposures increased in a dose-proportional manner. Rolapitant is slowly eliminated with a mean terminal half-life of approximately 7 days. Rolapitant is eliminated mainly through the hepatobiliary route, with minor contributions from renal elimination. Rolapitant is metabolised by CYP3A4 to form a major active metabolite, M19. In vitro studies suggest that rolapitant is not an inhibitor of CYP2E1.
Following a single dose administration of 180 mg rolapitant under fasting conditions to healthy subjects, rolapitant was measurable in plasma between 30 minutes and the peak plasma concentration (Cmax) for rolapitant which was reached in about 4 hours and mean Cmax was 968 ng/mL (CV:28).
Following multiple oral doses 9 to 45 mg once daily of rolapitant; accumulation of rolapitant was approximately 5-fold.
The systemic exposures (Cmax and AUC) to rolapitant increased in a dose-proportional manner when the dose of rolapitant increased from 4.5 mg to 180 mg. With an increase in dose by 4 times from the recommended clinical dose of 180 mg, the Cmax and AUC of rolapitant increased by 3.1 fold and 3.7 fold, respectively.
The absolute bioavailability of rolapitant is approximately 100%, indicating minimal first pass effect.
Concomitant administration of a high fat meal did not significantly affect the pharmacokinetics of rolapitant after administration of 180 mg rolapitant.
Rolapitant was highly protein bound to human plasma (99.8%). The apparent volume of distribution (Vd/F) was 460 L in healthy subjects, indicating an extensive tissue distribution of rolapitant. In a population pharmacokinetic analysis of rolapitant, the Vd/F was 387 L in cancer patients.
Rolapitant is metabolised by CYP3A4 to form a major active metabolite, M19 (C4-pyrrolidine-hydroxylated rolapitant). In a mass balance study, the metabolite M19 was the major circulating metabolite. The formation of M19 was significantly delayed with the median Tmax of 120 hours (range: 24-168 hours) and the mean half-life of M19 was 158 hours. The exposure ratio of M19 to rolapitant was approximately 50% in plasma.
Following single oral doses (4.5 to 180 mg) of rolapitant, the mean terminal half-life (t½) of rolapitant ranged from 169 to 183 hours (approximately 7 days) and was independent of dose. In a population pharmacokinetic analysis the apparent total clearance (CL/F) of rolapitant was 0.96 L/hour in cancer patients.
Rolapitant is eliminated primarily through the hepatobiliary route. Following administration of a single oral 180-mg dose of [14C]-rolapitant, on average 14.2% (range 9% to 20%) and 73% (range 52% to 89%) of the dose was recovered in the urine and feces, respectively over 6 weeks. In pooled samples collected over 2 weeks, 8.3% of the dose was recovered in the urine primarily as metabolites and 37.8% of the dose was recovered in the feces primarily as unchanged rolapitant. Unchanged rolapitant or M19 were not found in pooled urine sample. Drug metabolising enzymes (and drug transporters) other than CYP3A4 involved in rolapitant hepatobiliary elimination remain to be elucidated.
Population pharmacokinetic analyses indicated that age, sex and race had no significant impact on the pharmacokinetics of rolapitant. There are limited data in patients aged 75 years and older.
Following administration of a single dose of 180 mg rolapitant to patients with mild hepatic impairment (Child-Pugh Class A), the pharmacokinetics of rolapitant were comparable with those of healthy subjects. In patients with moderate hepatic impairment (Child-Pugh Class B), the mean Cmax was 25% lower while mean AUC of rolapitant was similar compared to those of healthy subjects. The median Tmax for M19 was delayed to 204 hours in patients with mild or moderate hepatic impairment compared to 168 hours in healthy subjects. The pharmacokinetics of rolapitant was not studied in patients with severe hepatic impairment (Child-Pugh Class C).
In population pharmacokinetic analyses, creatinine clearance (CLcr) at baseline did not show a significant effect on rolapitant pharmacokinetics in cancer patients with mild (CLcr: 60 to 90 mL/min) or moderate (CLcr: 30 to 60 mL/min) renal impairment compared to cancer patients with normal kidney function. Information is insufficient for the effect of severe renal impairment. The pharmacokinetics of rolapitant was not studied in patients with end-stage renal disease requiring haemodialysis.
A human Positron Emission Tomography (PET) study with rolapitant demonstrated that rolapitant crosses the blood brain barrier and occupies brain NK1 receptors. A dose-dependent increase in mean NK1 receptor occupancy was observed in the dose range from 4.5 mg to 180 mg of rolapitant. At rolapitant plasma concentrations of >15 ng/mL and 348 ng/mL, the NK1 receptor occupancies in the cortical regions were approximately >50% and 90% respectively. At the 180 mg dose of rolapitant, the mean NK1 receptor occupancy in the cortical regions was greater than 90% for at least 120 hours.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, teratogenic potential, and carcinogenic potential.
The mechanism of the significant difference of half-lives observed between the rat and monkey (6-8 h) and human (7 days) is not elucidated.
In rodents, rolapitant was tested in repeated dose oral toxicity studies up to 26 weeks in duration, and the liver, thyroid, kidneys, epididymis and uterus were identified as target organs. In a three-month rat study, clonic convulsions were observed in a single animal at 125 mg/kg/day (approximately 6 times the recommended human dose on a body surface area basis). In the one-month monkey study, convulsions were observed at 60 mg/kg/day (approximately 5.8 times the recommended human dose on a body surface area basis). The relevance of convulsions for humans is unknown.
In a fertility and early embryonic development study in female rats, rolapitant hydrochloride at an oral dose equivalent to 9 mg/kg per day free base (approximately 0.5 times the recommended human dose on a body surface area basis) caused a transient decrease in maternal body weight gain and increases in the incidence of pre- and post-implantation loss. At a dose equivalent to 4.5 mg/kg per day free base (approximately 0.2 times the recommended human dose on a body surface area basis), there were decreases in the number of corpora lutea and implantation sites.
In a pre- and post-natal development rat study, maternal toxicity was evident based on mortality/moribund condition, decreased body weight and food consumption, total litter loss, prolonged parturition, decreased length of gestation, and increased number of unaccounted for implantation sites at a dose equivalent to 22.5 mg/kg per day free base (approximately 1.2 times the recommended human dose on a body surface area basis). Effects on offspring at this dose included decreased postnatal survival, and decreased body weights and body weight gain, and may be related to the maternal toxicity observed. At a maternal dose equivalent to 9 mg/kg per day rolapitant free base (approximately 0.5 times the recommended human dose on a body surface area basis), there was a decrease in memory in female pups in a maze test and a decrease in pup body weight.
Based on the environmental risk assessment, rolapitant is considered as very persistent, bioaccumulative and not readily biodegradable.
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