Cardiovascular Safety of Anagrelide in Healthy Subjects: Effects of Caffeine and Food Intake on Pharmacokinetics and Adverse Reactions

• DOI: 10.1007/s40261-012-0032-2
• Publication Date: 2012-12-19T23:06:17Z
• Authors: Manuel Martínez-S...; Tomás Datino; Lourdes Figueiras...; Joubert G. Gama; Christopher Jones; Richard Franklin; Francisco Fernánd...
• Keywords: Anagrelide; Palpitations; Active metabolite

Essential thrombocythaemia (ET) is a rare clonal myeloproliferative disorder characterized by sustained elevation in platelet count and megakaryocyte hyperplasia. Anagrelide used the treatment of ET, where it has been shown to reduce count. metabolized cytochrome P450 (CYP) 1A2, previous studies effect food on bioavailability pharmacokinetics anagrelide were conducted prior identification active metabolite, 3-hydroxyanagrelide. The objectives this study determine caffeine its 3-hydroxyanagrelide, monitor electrocardiogram (ECG) parameters following drug administration, document relationship between palpitations, ECG changes intake Thirty-five healthy subjects who received 1 mg either 10-h fast or within 30 min standardized breakfast, including two cups coffee, studied. Time maximum (peak) plasma concentration (Cmax) was 4.0 h fed 1.5 fasted group (p < 0.05); similar results observed for mean Cmax 4.45 ± 2.32 ng/mL 5.08 2.99 fed/caffeine groups, respectively; peak concentrations higher 3-hydroxyanagrelide both groups. most frequent adverse events (AEs) headache (60 %) palpitations (40 %). There no serious AEs all ECGs normal, although significant reductions PR interval, QRS length QT interval Heart rate increased after administration states 0.01); however, heart significantly more state than 0.001 increase first hour administration). trend towards greater reporting those without (mean SD at h: 10.1 6.4 vs. 8.0 8.4 beats/min [p = 0.35]; 4 12.7 7.5 9.1 8.8 0.10], respectively). We conclude that food/caffeine delayed absorption anagrelide. generally well tolerated had small effects rate. Caffeine may be implicated frequency with versus fasting.