Chemical formula: C₂₀H₂₀FNO₃S Molecular mass: 373.441 g/mol PubChem compound: 6918456
Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets. Since platelets participate in the initiation and/or evolution of thrombotic complications of atherosclerotic disease, inhibition of platelet function can result in the reduction of the rate of cardiovascular events such as death, myocardial infarction, or stroke.
Following a 60 mg loading dose of prasugrel, inhibition of ADP-induced platelet aggregation occurs at 15 minutes with 5 pM ADP and 30 minutes with 20 pM ADP. The maximum inhibition by prasugrel of ADP-induced platelet aggregation is 83% with 5 pM ADP and 79% with 20 pM ADP, in both cases with 89% of healthy subjects and patients with stable atherosclerosis achieving at least 50% inhibition of platelet aggregation by 1 hour. Prasugrel-mediated inhibition of platelet aggregation exhibits low between-subject (9%) and within-subject (12%) variability with both 5 pM and 20 pM ADP. Mean steady-state inhibition of platelet aggregation was 74% and 69% respectively for 5 pM ADP and 20 pM ADP, and was achieved following 3 to 5 days of administration of the 10 mg prasugrel maintenance dose preceded by a 60 mg loading dose. More than 98% of subjects had ≥20% inhibition of platelet aggregation during maintenance dosing.
Platelet aggregation gradually returned to baseline values after treatment in 7 to 9 days after administration of a single 60 mg loading dose of prasugrel and in 5 days following discontinuation of maintenance dosing at steady-state.
Prasugrel is a prodrug and is rapidly metabolised in vivo to an active metabolite and inactive metabolites. The active metabolite’s exposure (AUC) has moderate to low between-subject (27%) and within-subject (19%) variability. Prasugrel’s pharmacokinetics are similar in healthy subjects, patients with stable atherosclerosis, and patients undergoing percutaneous coronary intervention.
The absorption and metabolism of prasugrel are rapid, with peak plasma concentration (Cmax) of the active metabolite occurring in approximately 30 minutes. The active metabolite’s exposure (AUC) increases proportionally over the therapeutic dose range. In a study of healthy subjects, AUC of the active metabolite was unaffected by a high fat, high calorie meal, but Cmax was decreased by 49% and the time to reach Cmax (Tmax) was increased from 0.5 to 1.5 hours. Prasugrel was administered without regard to food in TRITON. Therefore, prasugrel can be administered without regard to food; however, the administration of prasugrel loading dose in the fasted state may provide most rapid onset of action.
Active metabolite binding to human serum albumin (4% buffered solution) was 98%.
Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolysed in the intestine to a thiolactone, which is then converted to the active metabolite by a single step of cytochrome P450 metabolism, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. The active metabolite is further metabolised to two inactive compounds by S-methylation or conjugation with cysteine.
In healthy subjects, patients with stable atherosclerosis, and patients with ACS receiving prasugrel, there was no relevant effect of genetic variation in CYP3A5, CYP2B6, CYP2C9, or CYP2C19 on the pharmacokinetics of prasugrel or its inhibition of platelet aggregation.
Approximately 68% of the prasugrel dose is excreted in the urine and 27% in the faeces, as inactive metabolites. The active metabolite has an elimination half-life of about 7.4 hours (range 2 to 15 hours).
In a study of healthy subjects between the ages of 20 and 80 years, age had no significant effect on pharmacokinetics of prasugrel or its inhibition of platelet aggregation. In the large phase 3 clinical trial, the mean estimated exposure (AUC) of the active metabolite was 19% higher in very elderly patients (≥75 years of age) compared to subjects <75 years of age. Prasugrel should be used with caution in patients ≥75 years of age due to the potential risk of bleeding in this population. In a study in subjects with stable atherosclerosis, the mean AUC of the active metabolite in patients >75 years old taking 5 mg prasugrel was approximately half that in patients <65 years old taking 10 mg prasugrel, and the antiplatelet effect of 5 mg was reduced but was non-inferior compared to 10 mg.
No dose adjustment is necessary for patients with mild to moderate impaired hepatic function (Child Pugh Class A and B). Pharmacokinetics of prasugrel and its inhibition of platelet aggregation were similar in subjects with mild to moderate hepatic impairment compared to healthy subjects. Pharmacokinetics and pharmacodynamics of prasugrel in patients with severe hepatic impairment have not been studied. Prasugrel must not be used in patients with severe hepatic impairment.
No dosage adjustment is necessary for patients with renal impairment, including patients with end stage renal disease (ESRD). Pharmacokinetics of prasugrel and its inhibition of platelet aggregation are similar in patients with moderate renal impairment (GFR 30<50 ml/min/1.73m²) and healthy subjects. Prasugrel-mediated inhibition of platelet aggregation was also similar in patients with ESRD who required haemodialysis compared to healthy subjects, although Cmax and AUC of the active metabolite decreased 51% and 42%, respectively, in ESRD patients.
The mean exposure (AUC) of the active metabolite of prasugrel is approximately 30 to 40% higher in healthy subjects and patients with a body weight of <60 kg compared to those weighing ≥60 kg. Prasugrel should be used with caution in patients with a body weight of <60 kg due to the potential risk of bleeding in this population. In a study in subjects with stable atherosclerosis, the mean AUC of the active metabolite in patients <60 kg taking 5 mg prasugrel was 38% lower than in patients ≥60 kg taking 10 mg prasugrel, and the antiplatelet effect of 5 mg was similar to 10 mg.
In clinical pharmacology studies, after adjusting for body weight, the AUC of the active metabolite was approximately 19% higher in Chinese, Japanese, and Korean subjects compared to that of Caucasians, predominantly related to higher exposure in Asian subjects <60 kg. There is no difference in exposure among Chinese, Japanese, and Korean subjects. Exposure in subjects of African and Hispanic descent is comparable to that of Caucasians. No dose adjustment is recommended based on ethnicity alone.
In healthy subjects and patients, the pharmacokinetics of prasugrel are similar in men and women.
Pharmacokinetics and pharmacodynamics of prasugrel have not been evaluated in a paediatric population.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, or toxicity to reproduction. Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Embryo-foetal developmental toxicology studies in rats and rabbits showed no evidence of malformations due to prasugrel. At a very high dose (>240 times the recommended daily human maintenance dose on a mg/m² basis) that caused effects on maternal body weight and/or food consumption, there was a slight decrease in offspring body weight (relative to controls). In pre- and post-natal rat studies, maternal treatment had no effect on the behavioural or reproductive development of the offspring at doses up to an exposure 240 times the recommended daily human maintenance dose (based on mg/m²).
No compound-related tumours were observed in a 2-year rat study with prasugrel exposures ranging to greater than 75 times the recommended therapeutic exposures in humans (based on plasma exposures to the active and major circulating human metabolites). There was an increased incidence of tumours (hepatocellular adenomas) in mice exposed for 2 years to high doses (>75 times human exposure), but this was considered secondary to prasugrel-induced enzyme-induction. The rodent-specific association of liver tumours and drug-induced enzyme induction is well documented in the literature. The increase in liver tumours with prasugrel administration in mice is not considered a relevant human risk.
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