A phase 1 study of prasugrel in patients with sickle cell disease: pharmacokinetics and effects on ex vivo platelet reactivity.

Abstract

AIMS:

Prasugrel is a novel thienopyridine P2Y12 adenosine diphosphate (ADP) receptor antagonist that inhibits ADP-mediated platelet activation and aggregation. Accordingly, it may be useful in reducing platelet-related ischaemia in sickle cell disease (SCD). Exposure to prasugrel's active metabolite (Pras-AM) and its antiplatelet activity in SCD have not been investigated.

METHODS:

Thirteen adult patients with SCD and an equal number of matched healthy control subjects were studied before and after 12 days of 5.0 or 7.5 mg day(-1) prasugrel treatment. Platelet reactivity was assessed by light transmission aggregometry (LTA), impedance aggregometry (MEA), VerifyNow® P2Y12, vasodilator-stimulated phosphoprotein (VASP) phosphorylation and Plateletworks. Exposure to Pras-AM was also assessed.

RESULTS:

At baseline, patients with SCD showed increased platelet reactivity vs. healthy control subjects with VerifyNow (408 vs. 323 P2Y12 reaction units (PRU), respectively, P = 0.003) and MEA (106 vs. 77 area under the aggregation curve (AU.min), P = 0.002); lower platelet reactivity index with VASP flow cytometry (59 vs. 79% platelet reactivity index (PRI), P = 0.018); and no significant differences with LTA, VASP enzyme-linked immunosorbent assay or Plateletworks. Relative to baseline, prasugrel significantly reduced platelet reactivity by all assays in both populations (all P < 0.05). Prasugrel was well tolerated, with no bleeding-related events in patients with SCD. The mean concentration-time profiles of Pras-AM were comparable between healthy subjects and patients with SCD following a single 10 mg prasugrel dose and following the 12th dose of 7.5 or 5 mg prasugrel.

CONCLUSIONS:

Results demonstrate that in response to prasugrel, patients with SCD and healthy subjects have similar degrees of platelet inhibition and exposure to Pras-AM, and provide a basis for further study of prasugrel in patients with SCD.

• Authors: Joseph A Jakubowski, Chunmei Zhou, David S Small, Kenneth J Winters, D Richard Lachno, Andrew L Frelinger 3rd, Jo Howard, Timothy G Mant, Stipo Jurcevic, Christopher D Payne
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 75 Issue 6 Pg. 1433-44 (Jun 2013) ISSN: 1365-2125 [Electronic] England
• PMID: 23171128 (Publication Type: Clinical Trial, Phase I, Journal Article)
• Copyright: © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Chemical References

• Piperazines
• Purinergic P2 Receptor Antagonists
• Thiophenes
• Prasugrel Hydrochloride

Topics

• Adult
• Anemia, Sickle Cell (drug therapy, metabolism)
• Blood Platelets (drug effects)
• Enzyme-Linked Immunosorbent Assay
• Female
• Flow Cytometry
• Humans
• Male
• Piperazines (adverse effects, pharmacokinetics, pharmacology)
• Platelet Function Tests
• Prasugrel Hydrochloride
• Purinergic P2 Receptor Antagonists (adverse effects, pharmacokinetics, pharmacology)
• Thiophenes (adverse effects, pharmacokinetics, pharmacology)
• Young Adult