This phase 2 study was designed to characterize the relationship among prasugrel dose, prasugrel’s active metabolite (Pras-AM), and platelet inhibition while evaluating safety in children with sickle cell disease. It was open-label, multicenter, adaptive design, dose ranging, and conducted in 2 parts. Part A: Patients received escalating single doses leading to corresponding increases in Pras-AM exposure and VerifyNow®P2Y12 (VN) platelet inhibition and decreases in VNP2Y12 reaction units and vasodilator-stimulated phosphoprotein platelet reactivity index. Part B: Patients were assigned daily doses (0.06, 0.08, and 0.12 mg/kg) based on VN pharmacodynamic measurements at the start of 2 dosing periods, each 14±4 days. Platelet inhibition was significantly higher at 0.12 mg/kg (56.3%±7.4%; least squares mean±SE) compared with 0.06 mg/kg (33.8%±7.4%) or 0.08 mg/kg (37.9%±5.6%). Patients receiving 0.12 mg/kg achieved ≥30% platelet inhibition; only 1 patient receiving 0.06 mg/kg exceeded 60% platelet inhibition. High interpatient variability in response to prasugrel and the small range of exposures precluded rigorous characterization of the relationship among dose, Pras-AM, and platelet inhibition.
No hemorrhagic events occurred in Part A; 3 occurred in Part B, all mild and self-limited.
Most children with sickle cell disease may achieve clinically relevant platelet inhibition with titration of daily-dose prasugrel.
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*Children’s Hospital and Research Center, Oakland, CA
†Eli Lilly and Company, Indianapolis, IN
‡Division of Hematology and Oncology, Departments of Pediatrics and Internal Medicine, University of North Carolina, Chapel Hill, NC
§Boston Children’s Hospital, Boston, MA
∥Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
¶Department of Pediatrics and Child Health, Howard University, Washington, DC
#Division of Pediatric Hematology-Oncology, Department of Pediatrics, Medical University of South Carolina, Charleston, SC
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Supported by Daiichi Sankyo Inc. and Eli Lilly and Company.
D.H., J.A.J., D.S.S., K.J.W., L.E.H., B.A.M., and C.Z. are employees and shareholders of Eli Lilly and Company. L.S. is a consultant for Eli Lilly and Company. M.M.H. receives research funding from Eli Lilly and Company and Novartis and is a consultant at Pfizer and Novartis. R.R.-L. and C.T.Q. receive research funding from Eli Lilly and Company. S.R.R. receives research funding from Eli Lilly and Company and Purdue Pharma. J.K. receives research funding from Eli Lilly and Company and Novartis.
Reprints: Lori Styles, MD, Children’s Hospital Oakland Research Institute, 747 52nd Street, Oakland, CA 94609 (e-mail: email@example.com).
Received September 27, 2013
Accepted October 21, 2014