PMID- 23184666
OWN - NLM
STAT- MEDLINE
DCOM- 20130702
LR  - 20211021
IS  - 1179-1918 (Electronic)
IS  - 1173-2563 (Print)
IS  - 1173-2563 (Linking)
VI  - 33
IP  - 1
DP  - 2013 Jan
TI  - Cardiovascular safety of anagrelide in healthy subjects: effects of caffeine and 
      food intake on pharmacokinetics and adverse reactions.
PG  - 45-54
LID - 10.1007/s40261-012-0032-2 [doi]
AB  - 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. OBJECTIVES: 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). CONCLUSION: 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.
FAU - Martinez-Selles, Manuel
AU  - Martinez-Selles M
AD  - Cardiology Department, Hospital General Universitario Gregorio Maranon, Calle del 
      Doctor Esquerdo, 46, 28007, Madrid, Spain. mmselles@secardiologia.es
FAU - Datino, Tomas
AU  - Datino T
FAU - Figueiras-Graillet, Lourdes
AU  - Figueiras-Graillet L
FAU - Gama, Joubert G
AU  - Gama JG
FAU - Jones, Christopher
AU  - Jones C
FAU - Franklin, Richard
AU  - Franklin R
FAU - Fernandez-Aviles, Francisco
AU  - Fernandez-Aviles F
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PL  - New Zealand
TA  - Clin Drug Investig
JT  - Clinical drug investigation
JID - 9504817
RN  - 0 (Hematologic Agents)
RN  - 0 (Quinazolines)
RN  - 3G6A5W338E (Caffeine)
RN  - EC 1.14.14.1 (CYP1A2 protein, human)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP1A2)
RN  - K9X45X0051 (anagrelide)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Analysis of Variance
MH  - Area Under Curve
MH  - Arrhythmias, Cardiac/*chemically induced/diagnosis/physiopathology
MH  - Biotransformation
MH  - Caffeine/administration & dosage/*adverse effects
MH  - Chi-Square Distribution
MH  - Cross-Over Studies
MH  - Cytochrome P-450 CYP1A2/metabolism
MH  - Drug Interactions
MH  - Electrocardiography
MH  - Fasting/metabolism
MH  - Female
MH  - *Food-Drug Interactions
MH  - Half-Life
MH  - Headache/chemically induced
MH  - Heart Rate/*drug effects
MH  - Hematologic Agents/administration & dosage/*adverse 
      effects/blood/*pharmacokinetics
MH  - Humans
MH  - Hydroxylation
MH  - Intestinal Absorption
MH  - London
MH  - Male
MH  - Metabolic Clearance Rate
MH  - Postprandial Period
MH  - Quinazolines/administration & dosage/*adverse effects/blood/*pharmacokinetics
MH  - Young Adult
PMC - PMC3586167
EDAT- 2012/11/28 06:00
MHDA- 2013/07/03 06:00
PMCR- 2012/11/27
CRDT- 2012/11/28 06:00
PHST- 2012/11/28 06:00 [entrez]
PHST- 2012/11/28 06:00 [pubmed]
PHST- 2013/07/03 06:00 [medline]
PHST- 2012/11/27 00:00 [pmc-release]
AID - 32 [pii]
AID - 10.1007/s40261-012-0032-2 [doi]
PST - ppublish
SO  - Clin Drug Investig. 2013 Jan;33(1):45-54. doi: 10.1007/s40261-012-0032-2.