Population Pharmacokinetic Analyses to Evaluate the Influence of Intrinsic and Extrinsic Factors on Exposure of Prasugrel Active Metabolite in TRITON‐TIMI 38

Abstract

Serial pharmacokinetic (PK) sampling in 1159 patients from TRITON-TIMI 38 was undertaken. A multilinear regression model was used to quantitatively predict prasugrel's active metabolite (Pras-AM) concentrations from its 2 downstream inactive metabolites. Population-based methods were then applied to Pras-AM concentration data to characterize the PK. The potential influence of body weight, body mass index, age, sex, renal function, diabetes, tobacco use, and other disease status on Bayesian estimates of Pras-AM exposures was assessed. The PK of Pras-AM was adequately described by a multicompartmental model and consistent with results from previous studies. The systemic exposure of prasugrel was not appreciably affected by body mass index, gender, diabetes, smoking, and renal impairment. Pras-AM mean exposure in patients weighing <60 kg (4.1%) was 30% (90% confidence interval [CI] 1.16-1.45) higher than exposure in patients > or =60 kg. Mean Pras-AM exposures for patients > or =75 years (10.5%) were 19% (90% CI: 1.11-1.28) higher compared with patients <75 years.

Factors Affecting Platelet Reactivity 2 Hours After P2Y₁₂ Receptor Antagonist Loading in Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction – Impact of Pain-to-Loading Time –

“…[24][25][26] In the present analysis involving the early phase of STEMI, a similar positive association between increasing BMI and platelet reactivity 2 h after LD was identified. Morphine use was also positively associated with platelet reactivity 2 h after LD, in accordance with previous studies, most likely by delaying antiplatelet agent absorption.…”

New P2Y 12 Inhibitors

“…26 As a matter of fact, decreasing the maintenance dose of prasugrel to 5 mg daily in patients who weigh Ͻ60 kg (Food and Drug Administration and European Medicines Agency) or are Ͼ75 years of age (European Medicines Agency) has been recommended, although there is no experimental evidence that this dose adjustment is safe and effective.…”

Prasugrel

“…In the analysis of TRITON-TIMI 38, pharmacokinetics were not appreciably affected by diabetes, smoking, or renal impairment. 30 In equimolar concentrations, the active metabolites of prasugrel and clopidogrel have similar antiplatelet effects. 31 Therefore, the more rapid and consistent conversion of prasugrel from the inactive prodrug to its active metabolite and the ability of patients to generate higher concentrations of the active metabolite provide the mechanistic basis for the differences in the pharmacological profiles of the 2 drugs.…”