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.

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.

Fig. 1

Mean plasma concentration-time profiles of (a) anagrelide and (b) 3-hydroxyanagrelide, in healthy subjects following either a 10-h fast or within 30 min of a standardized breakfast, including two cups of coffee

Fig. 2

Mean electrocardiogram (ECG) parameters before and after anagrelide administration: (a) heart rate, (b) QRS length, (c) PR interval, (d) QT interval and (e) corrected QT interval (QTc). P value for the ANOVA test was <0.001 in all cases except QRS (p = 0.028). * p < 0.05 for the comparison with pre-drug value (Bonferroni analysis). Error bars = 95 % confidence intervals

Fig. 3

Mean electrocardiogram (ECG) changes after anagrelide administration with respect to the fasted state: (a) heart rate, (b) QRS length, (c) PR interval, (d) QT interval and (e) corrected QT (QTc) interval. Two-way ANOVA included fasted state and time up to 4 h post-dose. In the case of heart rate and QT interval, the p value was <0.01 for the fasted state, time and interaction. In the cases of PR interval, QRS length and QTc interval, only time had a significant effect (p < 0.01). PR interval, QRS length and QT interval decreased following administration of anagrelide (p < 0.001), whereas there were no significant differences in QTc. * p < 0.001 for the comparison of fasted versus fed/caffeine state (Bonferroni analysis). Error bars = 95 % confidence intervals