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0091270009337942v1
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PHARMACOKINETICS

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

Rebecca E. Wrishko, PhD, C. Steven Ernest, II, MS, David S. Small, PhD, Ying G. Li, MS, Govinda J. Weerakkody, PhD, Jeffrey R. Riesmeyer, MD, William L. Macias, MD, PhD, Shashank Rohatagi, PhD, Daniel E. Salazar, PhD, Elliott M. Antman, MD, Stephen D. Wiviott, MD, Eugene Braunwald, MD and Lan Ni, PhD

From Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (Dr Wrishko, Mr Ernest, Dr Small, Ms Li, Dr Weerakkody, Dr Riesmeyer, Dr Macias, Dr Ni); Daiichi Sankyo, Inc, Parsippany, New Jersey (Dr Rohatagi, Dr Salazar); and TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (Dr Antman, Dr Wiviott, Dr Braunwald).

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 ≥60 kg. Mean Pras-AM exposures for patients ≥75 years (10.5%) were 19% (90% CI: 1.11-1.28) higher compared with patients <75 years.

Key Words: Population pharmacokinetics • maximal platelet aggregation • prasugrel • TRITON-TIMI 38

Address for reprints: Rebecca Wrishko, PhD, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285; e-mail: wrishkore{at}lilly.com.


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