title: Increased active metabolite formation explains the greater platelet inhibition with prasugrel compared to high-dose clopidogrel.
abstract: Prasugrel pharmacodynamics and pharmacokinetics after a 60-mg loading dose (LD) and daily 10-mg maintenance doses (MD) were compared in a 3-way crossover study to clopidogrel 600-mg/75-mg and 300-mg/75-mg LD/MD in 41 healthy, aspirin-free subjects. Each LD was followed by 7 days of daily MD and a 14-day washout period. Inhibition of platelet aggregation (IPA) was assessed by turbidometric aggregometry (20 and 5 microM ADP). Prasugrel 60-mg achieved higher mean IPA (54%) 30 minutes post-LD than clopidogrel 300-mg (3%) or 600-mg (6%) (P < 0.001) and greater IPA by 1 hour (82%) and 2 hours (91%) than the 6-hour IPA for clopidogrel 300-mg (51%) or 600-mg (69%) (P < 0.01). During MD, IPA for prasugrel 10-mg (78%) exceeded that of clopidogrel (300-mg/75-mg, 56%; 600-mg/75-mg, 52%; P < 0.001). Active metabolite area under the concentration-time curve (AUC0-tlast) after prasugrel 60-mg (594 ng.hr/mL) was 2.2 times that after clopidogrel 600-mg. Prasugrel active metabolite AUC0-tlast was consistent with dose-proportionality from 10-mg to 60-mg, while clopidogrel active metabolite AUC0-tlast exhibited saturable absorption and/or metabolism. In conclusion, greater exposure to prasugrel's active metabolite results in faster onset, higher levels, and less variability of platelet inhibition compared with high-dose clopidogrel in healthy subjects.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, UK.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Payne
authors.forename: Ying Grace
authors.initials: YG
authors.lastname: Li
authors.forename: David S
authors.initials: DS
authors.lastname: Small
authors.forename: C Steven
authors.initials: CS
authors.lastname: Ernest
authors.forename: Nagy A
authors.initials: NA
authors.lastname: Farid
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Jakubowski
authors.forename: John T
authors.initials: JT
authors.lastname: Brandt
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Salazar
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Winters
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D019540:Area Under Curve; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D000077144:Clopidogrel; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D000068799:Prasugrel Hydrochloride; D013876:Thiophenes / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D013876:Thiophenes; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine