Prediction of prasugrel active metabolite concentrations from 2 downstream inactive metabolite concentrations using multilinear regression analysis.
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.
Ernest
C Steven
CS
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. cse@lilly.com
Heathman
Michael A
MA
Wrishko
Rebecca E
RE
D000293:Adolescent; D000328:Adult; D000368:Aged; D017326:Clinical Trials, Phase III as Topic; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000068799:Prasugrel Hydrochloride; D011355:Prodrugs; D013876:Thiophenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D011355:Prodrugs; C510685:R-138727; D013876:Thiophenes; D000068799:Prasugrel Hydrochloride