Relationship Between Exposure to Prasugrel Active Metabolite and Clinical Outcomes in the TRITON-TIMI 38 Substudy

In TRITON-TIMI 38, levels of the prasugrel active metabolite (pros-AM) were measured in a population pharmacokinetic substudy that characterized the intrinsic and extrinsic factors influencing exposure. Higher exposure to the pros-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 pros-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 pros-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 pros-AM. Within low body weight and very elderly subgroups, bleeding was largely confined to patients having the highest exposure to the pros-AM, indicating that a prasugrel lower dose in these subgroups may reduce the risk of bleeding while maintaining efficacy.