title: Relationship between exposure to prasugrel active metabolite and clinical outcomes in the TRITON-TIMI 38 substudy.
abstract: In TRITON-TIMI 38, levels of the prasugrel active metabolite (pras-AM) were measured in a population pharmacokinetic substudy that characterized the intrinsic and extrinsic factors influencing exposure. Higher exposure to the pras-AM was observed in low-weight or very elderly patients. The authors hypothesized that this higher exposure might explain the higher risk of non-coronary artery bypass graft (CABG)-related TIMI-related bleeding observed in these 2 patient populations. The relationship between estimated exposure to the pras-AM and clinical outcomes was assessed in 1159 prasugrel-treated patients enrolled in the substudy using multivariable logistic regression analysis. There was no relationship between pras-AM exposure and efficacy through 3 days or after 3 days. Higher estimated pras-AM exposure was associated with a higher incidence of non-CABG-related TIMI major or minor bleeding after 3 days (P < .05) but not through 3 days from start of study drug. Factors associated with increased risk for non-CABG-related TIMI bleeding (≥75 years and <60 kg) also identified subgroups with higher exposure to the pras-AM. Within low body weight and very elderly subgroups, bleeding was largely confined to patients having the highest exposure to the pras-AM, indicating that a prasugrel lower dose in these subgroups may reduce the risk of bleeding while maintaining efficacy.
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana 46285, USA. ries@lilly.com
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Riesmeyer
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Salazar
authors.forename: Govinda J
authors.initials: GJ
authors.lastname: Weerakkody
authors.forename: Lan
authors.initials: L
authors.lastname: Ni
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Wrishko
authors.forename: C Steven
authors.initials: CS
authors.lastname: Ernest
authors.forename: Junxiang
authors.initials: J
authors.lastname: Luo
authors.forename: Ying G
authors.initials: YG
authors.lastname: Li
authors.forename: David S
authors.initials: DS
authors.lastname: Small
authors.forename: Shashank
authors.initials: S
authors.lastname: Rohatagi
authors.forename: William L
authors.initials: WL
authors.lastname: Macias
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000367:Age Factors; D000368:Aged; D001711:Biotransformation; D001835:Body Weight; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006470:Hemorrhage / Q000139:chemically induced* / Q000453:epidemiology / Q000503:physiopathology; D006801:Humans; D015994:Incidence; D008297:Male; D008954:Models, Biological; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000068799:Prasugrel Hydrochloride; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D058925:Receptors, Purinergic P2Y12 / Q000737:chemistry; D012720:Severity of Illness Index; D013876:Thiophenes / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*
chemical_list: D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D011355:Prodrugs; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D013876:Thiophenes; D000068799:Prasugrel Hydrochloride