Prediction of prasugrel active metabolite concentrations from 2 downstream inactive metabolite concentrations using multilinear regression analysis

J Clin Pharmacol. 2009 Aug;49(8):973-83. doi: 10.1177/0091270009340416.

Abstract

Prasugrel is a thienopyridine prodrug that is metabolized to an active metabolite (Pras-AM), which inhibits adenosine diphosphate (ADP)-induced platelet aggregation. The study objective was to describe a multilinear regression correlation model that was used to quantitatively predict concentrations of Pras-AM from downstream inactive metabolites, R-119251 and R-106583, for the purpose of estimating Pras-AM exposure in patients in the TRITON-TIMI 38 substudies. The model development included 1462 Pras-AM, 1345 R-119251, and 1456 R-106583 concentration data points from 103 healthy participants with a prasugrel dose range of 15 to 80 mg. The model was shown to provide good correlation between predicted and observed concentrations with only a minor deviation of approximately 6% from the unity line and described the variability within approximately 4.5%. Examination of the data indicated that regardless of ethnicity, age, weight, moderate hepatic impairment, or renal impairment, predictions were reliable. Predicted Pras-AM concentrations in TRITON-TIMI 38 were comparable with historical data.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Clinical Trials, Phase III as Topic
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Linear Models
  • Male
  • Middle Aged
  • Models, Biological*
  • Piperazines / administration & dosage
  • Piperazines / pharmacokinetics*
  • Platelet Aggregation Inhibitors / administration & dosage
  • Platelet Aggregation Inhibitors / pharmacokinetics*
  • Prasugrel Hydrochloride
  • Prodrugs
  • Thiophenes / administration & dosage
  • Thiophenes / pharmacokinetics*
  • Young Adult

Substances

  • Piperazines
  • Platelet Aggregation Inhibitors
  • Prodrugs
  • R-138727
  • Thiophenes
  • Prasugrel Hydrochloride