title: Cardiovascular safety of anagrelide in healthy subjects: effects of caffeine and food intake on pharmacokinetics and adverse reactions.
abstract: BACKGROUND
  Essential thrombocythaemia (ET) is a rare clonal myeloproliferative disorder characterized by a sustained elevation in platelet count and megakaryocyte hyperplasia. Anagrelide is used in the treatment of ET, where it has been shown to reduce platelet count. Anagrelide is metabolized by cytochrome P450 (CYP) 1A2, and previous studies of the effect of food on the bioavailability and pharmacokinetics of anagrelide were conducted prior to the identification of the active metabolite, 3-hydroxyanagrelide.
  
  
  OBJECTIVE
  The objectives of this study were to determine the effect of food and caffeine on the pharmacokinetics of anagrelide and its active metabolite, 3-hydroxyanagrelide, to monitor electrocardiogram (ECG) parameters following drug administration, and to document the relationship between palpitations, ECG changes and caffeine intake
  
  
  METHODS
  Thirty-five healthy subjects who received 1 mg of anagrelide following either a 10-h fast or within 30 min of a standardized breakfast, including two cups of coffee, were studied.
  
  
  RESULTS
  Time to maximum (peak) plasma concentration (C(max)) of anagrelide was 4.0 h in the fed and 1.5 h in the fasted group (p < 0.05); similar results were observed for 3-hydroxyanagrelide. The mean C(max) of anagrelide was 4.45 ± 2.32 ng/mL and 5.08 ± 2.99 ng/mL in the fed/caffeine and fasted groups, respectively; peak concentrations were higher for 3-hydroxyanagrelide in both the fed/caffeine and fasted groups. The most frequent adverse events (AEs) were headache (60 %) and palpitations (40 %). There were no serious AEs and all ECGs were normal, although significant reductions in PR interval, QRS length and QT interval were observed in both groups. Heart rate increased after anagrelide administration in both fed/caffeine and fasted states (p < 0.01); however, increased heart rate was significantly more frequent in the fed/caffeine state than in the fasted state (p < 0.001 for heart rate increase in the first hour after drug administration). There was a trend towards a greater heart rate increase in subjects reporting palpitations than in those without (mean heart rate ± SD at 1 h: 10.1 ± 6.4 vs. 8.0 ± 8.4 beats/min [p = 0.35]; at 4 h: 12.7 ± 7.5 vs. 9.1 ± 8.8 beats/min [p = 0.10], respectively).
  
  
  CONCLUSIONS
  We conclude that food/caffeine delayed absorption of anagrelide. Anagrelide was generally well tolerated and had small effects on ECG parameters and heart rate. Caffeine may be implicated in a higher increase in heart rate and increased frequency of palpitations observed following administration of anagrelide with food/caffeine versus fasting.
authors.affiliation: Cardiology Department, Hospital General Universitario Gregorio Marañón, Calle del Doctor Esquerdo, 46, 28007, Madrid, Spain. mmselles@secardiologia.es
authors.forename: Manuel
authors.initials: M
authors.lastname: Martínez-Sellés
authors.forename: Tomás
authors.initials: T
authors.lastname: Datino
authors.forename: Lourdes
authors.initials: L
authors.lastname: Figueiras-Graillet
authors.forename: Joubert G
authors.initials: JG
authors.lastname: Gama
authors.forename: Christopher
authors.initials: C
authors.lastname: Jones
authors.forename: Richard
authors.initials: R
authors.lastname: Franklin
authors.forename: Francisco
authors.initials: F
authors.lastname: Fernández-Avilés
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D001711:Biotransformation; D002110:Caffeine / Q000008:administration & dosage / Q000009:adverse effects*; D016009:Chi-Square Distribution; D018592:Cross-Over Studies; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004347:Drug Interactions; D004562:Electrocardiography; D005215:Fasting / Q000378:metabolism; D005260:Female; D018565:Food-Drug Interactions; D006207:Half-Life; D006261:Headache / Q000139:chemically induced; D006339:Heart Rate / Q000187:drug effects*; D006401:Hematologic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D006900:Hydroxylation; D007408:Intestinal Absorption; D008131:London; D008297:Male; D008657:Metabolic Clearance Rate; D019518:Postprandial Period; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D006401:Hematologic Agents; D011799:Quinazolines; D002110:Caffeine; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; C021139:anagrelide