title: Integrated analysis of pharmacokinetic data across multiple clinical pharmacology studies of prasugrel, a new thienopyridine antiplatelet agent.
abstract: An integrated analysis of pharmacokinetic (PK) parameter estimates for prasugrel, from 16 phase I clinical pharmacology studies, consolidated exposure estimates from 506 healthy male and female participants and evaluated the effect of specific intrinsic and extrinsic factors on exposure to prasugrel's active metabolite (AM, R-138727). A linear mixed effect model was fitted with study and subject nested within study as random effects and subject factors as fixed effects. Prasugrel AM exposure was similar in males and females, in participants <65 years and ≥65 years, in smokers and nonsmokers, in drinkers and nondrinkers of alcohol, and in Asians, Caucasians, and participants of African and Hispanic descent. Prasugrel AM exposure increased as body weight decreased and was 40% higher in participants <60 kg than in participants ≥60 kg. Exposure in Asians was 40% higher than that in Caucasians, but this difference could be explained by the lower overall weight of the Asian participants and a disproportionately large difference between ethnic groups in lighter participants, especially those <60 kg. These results characterize prasugrel's PK across a range of studies and highlight body weight as the most influential covariate on prasugrel AM exposure, with implications for prasugrel maintenance dosing in clinical practice.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. dsmall@lilly.com
authors.forename: David S
authors.initials: DS
authors.lastname: Small
authors.forename: Ying G
authors.initials: YG
authors.lastname: Li
authors.forename: C Steven
authors.initials: CS
authors.lastname: Ernest
authors.forename: John H
authors.initials: JH
authors.lastname: April
authors.forename: Nagy A
authors.initials: NA
authors.lastname: Farid
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Payne
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Winters
authors.forename: Shashank
authors.initials: S
authors.lastname: Rohatagi
authors.forename: Lan
authors.initials: L
authors.lastname: Ni
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001711:Biotransformation; D001835:Body Weight; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics*; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D000068799:Prasugrel Hydrochloride; D011355:Prodrugs / Q000493:pharmacokinetics*; D058921:Purinergic P2Y Receptor Antagonists / Q000097:blood / Q000493:pharmacokinetics*; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism; D013876:Thiophenes / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D011355:Prodrugs; D058921:Purinergic P2Y Receptor Antagonists; C510685:R-138727; D058925:Receptors, Purinergic P2Y12; D013876:Thiophenes; D000068799:Prasugrel Hydrochloride