Pharmacokinetics, bioequivalence, tolerability, and effects on platelet counts of two formulations of anagrelide in healthy volunteers and patients with thrombocythemia associated with chronic myeloproliferation

Petrides, Petro E.; Gisslinger, Heinz; Steurer, Michael; Linkesch, Werner; Krumpl, Günther; Schüller, Agnes; Widmann, Rudolf

doi:10.1016/j.clinthera.2009.02.008

Cited by 10 publications

(24 citation statements)

References 18 publications

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“…The findings of the current study with regard to palpitations are analogous to a previous study comparing delayed- and immediate-release formulations of anagrelide, which found no difference between arms in the incidence of palpitations despite a lower frequency of AEs with the delayed-release formulation [4]. In our study, the median peak plasma concentration was significantly delayed by food intake.…”

Section: Discussionsupporting

confidence: 88%

“…In vitro studies have shown that anagrelide is metabolized by cytochrome P450 (CYP) 1A2 and produces the active metabolite 6,7-dichloro-3-hydroxy-1,5-dihydro-imidazol[2,1-b] quinazolin-2-one (3-hydroxyanagrelide) [4, 5]. Caffeine is a known substrate of CYP1A2 [6] and the possible effects of the constituents of a normal high-fat breakfast with coffee on the rate and extent of absorption of anagrelide, as well as the rate and extent of formation of the active metabolite, was considered worthy of investigation.…”

Section: Introductionmentioning

confidence: 99%

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

Martínez‐Sellés

Datino

Figueiras-Graillet

et al. 2012

Clinical Drug Investigation

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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.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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

Martínez‐Sellés

Datino

Figueiras-Graillet

et al. 2012

Clinical Drug Investigation

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“…Okamoto et al reported a C max of 2‐amino‐5,6‐dichloro‐3,4‐dihydroquinazolin of 1.4 ng/mL after treatment with 0.5 mg of anagrelide, which is in agreement with our results 22. The C max of 3‐hydroxyanagrelide in this trial was much higher (19 ng/mL) compared with an approximate C max of 8 ng/mL in another trial investigating the PK after 2 mg of anagrelide 17. However, assuming dose‐proportional PK, it is very comparable to the reported PK of a trial using 1 mg of anagrelide as treatment 16…”

Section: Discussionsupporting

confidence: 92%

Pharmacokinetics of a Novel Anagrelide Extended‐Release Formulation in Healthy Subjects: Food Intake and Comparison With a Reference Product

Petrides

Schoergenhofer

Widmann

et al. 2017

Clinical Pharm in Drug Dev

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Anagrelide is an established therapy for essential thrombocythemia. Common adverse effects have been linked to peak plasma concentrations of anagrelide and its 3OH metabolite. Our study was performed to investigate the pharmacokinetics (PK) of a novel anagrelide extended‐release (AER) formulation and its active metabolites. Thirty healthy volunteers were randomized to receive either 2 mg AER (under fasting and fed conditions) or 2 mg commercially available reference product (CARP) in an open‐label, 3‐way crossover trial with washout periods of 6 days. Plasma concentrations of anagrelide and its active metabolites were assessed by tandem mass spectrometry. The PK differed significantly between all treatment periods. Bioavailability of AER was 55% of the CARP under fasting conditions and 60% under fed conditions. Cmax, AUCt, and AUC∞ were significantly higher and Tmax and T1/2 were significantly shorter after the CARP compared with AER. Food had a significant impact on the PK of AER, increasing the Cmax and AUCt while reducing the T1/2, plateau, and mean residence time. Both formulations were well tolerated, with a trend toward more frequently occurring adverse events after the CARP. The PK of AER and the CARP differed significantly in all parameters. Food enhanced the bioavailability of AER.

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“…Study patients were randomly assigned to receive either a non-immediate release formulation of anagrelide 23 (Thromboreductin, AOP Orphan Pharmaceuticals AG, Austria) or hydroxyurea (BMS, UK) and were stratified by center and age groups (age ,60 years vs .60 years). After initiation of treatment with study drugs, patients were assessed weekly for efficacy and safety in the first month.…”

Section: Random Selection and Interventionsmentioning

confidence: 99%

Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial

Gisslinger

Gotić²,

Hołowiecki

et al. 2013

Blood

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219

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Pharmacokinetics, bioequivalence, tolerability, and effects on platelet counts of two formulations of anagrelide in healthy volunteers and patients with thrombocythemia associated with chronic myeloproliferation

Cited by 10 publications

References 18 publications

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

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

Pharmacokinetics of a Novel Anagrelide Extended‐Release Formulation in Healthy Subjects: Food Intake and Comparison With a Reference Product

Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial

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