Increased active metabolite formation explains the greater platelet inhibition with prasugrel compared to high-dose clopidogrel

• Published in: Journal of cardiovascular pharmacology Vol. 50; no. 5; p. 555
• Main Authors: Payne, Christopher D, Li, Ying Grace, Small, David S, Ernest, 2nd, C Steven, Farid, Nagy A, Jakubowski, Joseph A, Brandt, John T, Salazar, Daniel E, Winters, Kenneth J
• Format: Journal Article
• Language: English
• Published: United States 01.11.2007
• Subjects: Adenosine Diphosphate - pharmacology; Adult; Area Under Curve; Blood Platelets - cytology; Blood Platelets - drug effects; Cross-Over Studies; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Piperazines - metabolism; Piperazines - pharmacokinetics; Piperazines - pharmacology; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - metabolism; Platelet Aggregation Inhibitors - pharmacokinetics; Platelet Aggregation Inhibitors - pharmacology; Prasugrel Hydrochloride; Thiophenes - metabolism; Thiophenes - pharmacokinetics; Thiophenes - pharmacology; Ticlopidine - analogs & derivatives; Ticlopidine - metabolism; Ticlopidine - pharmacokinetics; Ticlopidine - pharmacology
• ISSN: 0160-2446
• DOI: 10.1097/FJC.0b013e3181492209

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.