In healthy subjects, patients with stable atherosclerosis, and patients with ACS receiving prasugrel, there was no relevant effect of genetic variation in CYP2B6, CYP2C9, CYP2C19, or CYP3A5 on the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation.
Platelet inhibition by prasugrel is rapid and irreversible, lasting for the life of the platelet, and is unlikely to be increased in the event of an overdose. In rats, lethality was observed after administration of 2000 mg/kg. Symptoms of acute toxicity in dogs included emesis, increased serum alkaline phosphatase, and hepatocellular atrophy. Symptoms of acute toxicity in rats included mydriasis, irregular respiration, decreased locomotor activity, ptosis, staggering gait, and lacrimation.
Platelet transfusion may restore clotting ability. The prasugrel active metabolite is not likely to be removed by dialysis.
Prasugrel tablets contain prasugrel, a thienopyridine class inhibitor of platelet activation and aggregation mediated by the P2Y 12 ADP receptor. Prasugrel is formulated as the hydrochloride salt, a racemate, which is chemically designated as 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride. Prasugrel hydrochloride has the empirical formula C 20 H 20 FNO 3 S•HCl representing a molecular weight of 409.90. The chemical structure of prasugrel hydrochloride is:
Prasugrel hydrochloride is a white to practically white solid. It is soluble at pH 2, slightly soluble at pH 3 to 4, and practically insoluble at pH 6 to 7.5. It also dissolves freely in methanol and is slightly soluble in 1- and 2-propanol and acetone. It is practically insoluble in diethyl ether and ethyl acetate.
Prasugrel tablets are available for oral administration as 5-mg or 10-mg elongated hexagonal, film-coated, non-scored tablets, debossed on each side. Each yellow 5-mg tablet is manufactured with 5.49 mg prasugrel hydrochloride, equivalent to 5-mg prasugrel and each beige 10-mg tablet with 10.98 mg prasugrel hydrochloride, equivalent to 10-mg of prasugrel.
Other ingredients include microcrystalline cellulose, hypromellose, low substituted hydroxyl propyl cellulose and sucrose stearate. The color coatings contain lactose monohydrate, hypromellose, titanium dioxide, triacetin, iron oxide yellow, and iron oxide red (only in 10-mg tablet).
Prasugrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y 12 class of ADP receptors on platelets.
Prasugrel produces inhibition of platelet aggregation to 20 μM or 5 μM ADP, as measured by light transmission aggregometry. Following a 60 mg loading dose of prasugrel, approximately 90% of patients had at least 50% inhibition of platelet aggregation by 1 hour. Maximum platelet inhibition was about 80% ( see Figure 2). Mean steady-state inhibition of platelet aggregation was about 70% following 3 to 5 days of dosing at 10-mg daily after a 60 mg loading dose of prasugrel tablets.
Figure 2: Inhibition (Mean±SD) of 20 μM ADP-induced Platelet Aggregation (IPA) Measured by Light Transmission Aggregometry after Prasugrel 60 mg.
Platelet aggregation gradually returns to baseline values over 5-9 days after discontinuation of prasugrel, this time course being a reflection of new platelet production rather than pharmacokinetics of prasugrel. Discontinuing clopidogrel 75-mg and initiating a prasugrel 10-mg maintenance dose with or without a prasugrel 60 mg loading dose results in a decrease of 14 percentage points in maximum platelet aggregation (MPA) by Day 7. This decrease in MPA is not greater than that typically produced by a 10-mg maintenance dose of prasugrel alone. The relationship between inhibition of platelet aggregation and clinical activity has not been established.
5-mg in Low Body Weight Patients — In patients with stable coronary artery disease, mean platelet inhibition in subjects <60 kg taking 5-mg prasugrel was similar to that of subjects ≥60 kg taking 10-mg prasugrel. The relationship between inhibition of platelet aggregation and clinical activity has not been established.
Prasugrel is a prodrug and is rapidly metabolized to a pharmacologically active metabolite and inactive metabolites. The active metabolite has an elimination half-life of about 7 hours (range 2-15 hours). Healthy subjects, patients with stable atherosclerosis, and patients undergoing PCI show similar pharmacokinetics.
Absorption and Binding — Following oral administration, ≥79% of the dose is absorbed. The absorption and metabolism are rapid, with peak plasma concentrations (C max ) of the active metabolite occurring approximately 30 minutes after dosing. The active metabolite’s exposure (AUC) increases slightly more than proportionally over the dose range of 5 to 60 mg. Repeated daily doses of 10 mg do not lead to accumulation of the active metabolite. In a study of healthy subjects given a single 15 mg dose, the AUC of the active metabolite was unaffected by a high fat, high calorie meal, but C max was decreased by 49% and T max was increased from 0.5 to 1.5 hours. Prasugrel tablets can be administered without regard to food. The active metabolite is bound about 98% to human serum albumin.
Metabolism and Elimination — Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolyzed in the intestine to a thiolactone, which is then converted to the active metabolite by a single step, primarily by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. The estimates of apparent volume of distribution of prasugrel’s active metabolite ranged from 44 to 68 L and the estimates of apparent clearance ranged from 112 to 166 L/hr in healthy subjects and patients with stable atherosclerosis. The active metabolite is metabolized to two inactive compounds by S-methylation or conjugation with cysteine. The major inactive metabolites are highly bound to human plasma proteins. Approximately 68% of the prasugrel dose is excreted in the urine and 27% in the feces as inactive metabolites.
Geriatric — In a study of 32 healthy subjects between the ages of 20 and 80 years, age had no significant effect on pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation. In TRITON-TIMI 38, the mean exposure (AUC) of the active metabolite was 19% higher in patients ≥75 years of age than in patients <75 years of age. In a study in subjects with stable atherosclerosis, the mean exposure (AUC) to the active metabolite of prasugrel in subjects ≥75 years old taking a 5-mg maintenance dose was approximately half that seen in subjects 45 to 64 years old taking a 10-mg maintenance dose [See Warnings and Precautions ( 5.1) and Use in Specific Populations ( 8.5)] .
Body Weight — The mean exposure (AUC) to the active metabolite is approximately 30 to 40% higher in subjects with a body weight of <60 kg than in those weighing ≥60 kg. In a study in subjects with stable atherosclerosis, the AUC of the active metabolite on average was 38% lower in subjects <60 kg taking 5-mg (N=34) than in subjects ≥60 kg taking 10-mg (N=38) [see Dosage and Administration ( 2), Warnings and Precautions ( 5.1), Adverse Reactions ( 6.1), and Use in Specific Populations ( 8.6)] .
Gender — Pharmacokinetics of prasugrel’s active metabolite are similar in men and women.
Ethnicity — Exposure in subjects of African and Hispanic descent is similar to that in Caucasians. 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 than in Caucasian subjects.
Smoking — Pharmacokinetics of prasugrel’s active metabolite are similar in smokers and nonsmokers.
Renal Impairment — Pharmacokinetics of prasugrel’s active metabolite and its inhibition of platelet aggregation are similar in patients with moderate renal impairment (CrCL=30 to 50 mL/min) and healthy subjects. In patients with end-stage renal disease, exposure to the active metabolite (both C max and AUC (0-t last )) was about half that in healthy controls and patients with moderate renal impairment [see Warnings and Precautions ( 5.1) and Use in Specific Populations ( 8.7)] .
Hepatic Impairment — Pharmacokinetics of prasugrel’s active metabolite and inhibition of platelet aggregation were similar in patients with mild to moderate hepatic impairment compared to healthy subjects. The pharmacokinetics and pharmacodynamics of prasugrel’s active metabolite in patients with severe hepatic disease have not been studied [ see Warnings and Precautions ( 5.1) and Use in Specific Populations ( 8.8)] .
Potential for Other Drugs to Affect Prasugrel
Inhibitors of CYP3A — Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4 and CYP3A5, did not affect prasugrel-mediated inhibition of platelet aggregation or the active metabolite’s AUC and T max , but decreased the C max by 34% to 46%. Therefore, CYP3A inhibitors such as verapamil, diltiazem, indinavir, ciprofloxacin, clarithromycin, and grapefruit juice are not expected to have a significant effect on the pharmacokinetics of the active metabolite of prasugrel [see Drug Interactions ( 7.4)] .
Inducers of Cytochromes P450 — Rifampicin (600 mg daily), a potent inducer of CYP3A and CYP2B6 and an inducer of CYP2C9, CYP2C19, and CYP2C8, did not significantly change the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation. Therefore, known CYP3A inducers such as rifampicin, carbamazepine, and other inducers of cytochromes P450 are not expected to have significant effect on the pharmacokinetics of the active metabolite of prasugrel [see Drug Interactions ( 7.4)] .
Drugs that Elevate Gastric pH — Daily coadministration of ranitidine (an H 2 blocker) or lansoprazole (a proton pump inhibitor) decreased the C max of the prasugrel active metabolite by 14% and 29%, respectively, but did not change the active metabolite’s AUC and T max . In TRITON-TIMI 38, prasugrel was administered without regard to coadministration of a proton pump inhibitor or H 2 blocker [see Drug Interactions ( 7.4)] .
Statins — Atorvastatin (80 mg daily), a drug metabolized by CYP450 3A4, did not alter the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation [see Drug Interactions ( 7.4)] .
Heparin — A single intravenous dose of unfractionated heparin (100 U/kg) did not significantly alter coagulation or the prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared with either drug alone [see Drug Interactions ( 7.4)] .
Aspirin — Aspirin 150 mg daily did not alter prasugrel-mediated inhibition of platelet aggregation; however, bleeding time was increased compared with either drug alone [see Drug Interactions ( 7.4)] .
Warfarin — A significant prolongation of the bleeding time was observed when prasugrel was coadministered with 15-mg of warfarin [see Drug Interactions ( 7.1)] .
Potential for Prasugrel to Affect Other Drugs
In vitro metabolism studies demonstrate that prasugrel’s main circulating metabolites are not likely to cause clinically significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A, or induction of CYP1A2 or CYP3A.
Drugs Metabolized by CYP2B6 — Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel decreased exposure to hydroxybupropion, a CYP2B6-mediated metabolite of bupropion, by 23%, an amount not considered clinically significant. Prasugrel is not anticipated to have significant effect on the pharmacokinetics of drugs that are primarily metabolized by CYP2B6, such as halothane, cyclophosphamide, propofol, and nevirapine.
Effect on Digoxin — The potential role of prasugrel as a Pgp substrate was not evaluated. Prasugrel is not an inhibitor of Pgp, as digoxin clearance was not affected by prasugrel coadministration [see Drug Interactions ( 7.4)] .
Morphine – Co-administration of 5 mg intravenous morphine with 60 mg loading dose of prasugrel in healthy adults decreased the C max of prasugrel’s active metabolite by 31% with no change in AUC, T max , or inhibition of ADP-induced platelet aggregation. ADP induced platelet aggregation was higher up to 2 hours following 60 mg loading dose of prasugrel in stable patients more than 1 year after an ACS who were co-administered morphine. In the patients with a 2-hour delay in the onset of platelet aggregation (5 of 11), T max was delayed and prasugrel active metabolite levels were significantly lower at 30 min (5 vs 120 ng/mL) following co-administration with morphine.
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