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

Abstract

BackgroundEssential 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.ObjectivesThe 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 intakeMethodsThirty-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.ResultsTime to maximum (peak) plasma concentration (Cmax) 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 Cmax 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).ConclusionWe 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.

Ventricular tachyarrhythmia in a 78-year-old woman with essential thrombocythaemia

“…Anagrelide absorption occurs rapidly and reaches maximum concentration in plasma within 1 hour after administration 7. After being absorbed, anagrelide is metabolised to the active metabolite 3-hydroxy-anagrelide in the liver primarily, by the cytochrome P450 1A2,7 which is further metabolised to an inactive metabolite, RL603.…”

“…After being absorbed, anagrelide is metabolised to the active metabolite 3-hydroxy-anagrelide in the liver primarily, by the cytochrome P450 1A2,7 which is further metabolised to an inactive metabolite, RL603. Anagrelide and the active metabolite 3-hydroxy-anagrelide have half lives of around 3 hours in healthy individuals 7…”

“…The mechanism behind the aetiology of palpitations are scarring and myocyte hypertrophy, that can cause abnormalities in the conduction system, increasing the probability of rhythm disturbance and generation of arrhythmias, perceived as palpitations 16. For this reason, there is a possibility that cardiac rhythm side effects are more pronounced in the elderly population on treatment with anagrelide 7. The negative inducibility of ventricular tachyarrhythmia on electrophysiology study is expected for torsades de pointes.…”

The Effect of Ergogenic Supplements and Mediterranean Diet on Cycling Performance. Differences According to Duration and Intensity.

“…The ergogenic impact of caffeine is supported by a plethora of studies [8,26,30,34,35]. However, caffeine intake can provoke side effects such as headache, hypertension, tachycardia and gastrointestinal upset [11,51] and acts differently in every athlete [70].…”

Caffeine Supplementation as an Ergogenic Aid for Muscular Strength and Endurance: A Recommendation for Coaches and Athletes

“…This identifies a possible area of concern for those participating in maximal effort weightlifting, due to the increase in blood pressure reported during these tasks [52]. Although uncommon and often minor, other more serious, complications include anxiety, restlessness, insomnia, and tachycardia [53]. Some evidence of gastrointestinal upset has also been documented with effects being greater in low habitual users [54].…”