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

Abstract

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.

A phase III randomized, multicentre, double blind, active controlled trial to compare the efficacy and safety of two different anagrelide formulations in patients with essential thrombocythaemia – the TEAM‐ET 2·0 trial

“…In each group, the trial drug was titrated based on platelet counts and tolerability. The mean doses during the maintenance period were comparable (2 mg RP, 3·5 mg A‐PR), considering the relative bioavailability of A‐PR (58%) compared to immediate‐release anagrelide (Petrides et al , ). The mean dose of the RP was also similar in other clinical trials investigating the effects of other anagrelide products with a similar titration plan (Okamoto et al , ; Kanakura et al , ).…”

“…The initial dose for anagrelide‐naïve patients was 1 mg of the RP or 2 mg A‐PR. Based on the relative bioavailability of 55% of A‐PR compared to the RP these doses were assumed to be equivalent (Petrides et al , ). Ten dose levels were defined, ranging from 0·5 to 5 mg for the RP and from 1 to 10 mg for the A‐PR (Fig ).…”

“…The occurrence of such side‐effects may be associated with high doses, high plasma concentrations of anagrelide or its active metabolites, whereas the platelet‐reducing effects of anagrelide do not depend on high plasma concentrations (Petrides, ; Petrides et al , ). Therefore a prolonged release formulation of anagrelide (A‐PR) was developed (Petrides et al , ). In a phase I trial, the relative bioavailability compared to a reference product (RP) was 55% under fasting conditions and 60% under fed conditions (Petrides et al , ).…”

“…Therefore a prolonged release formulation of anagrelide (A‐PR) was developed (Petrides et al , ). In a phase I trial, the relative bioavailability compared to a reference product (RP) was 55% under fasting conditions and 60% under fed conditions (Petrides et al , ). As expected for a prolonged release formulation, the maximum concentration (C max ) and the area under the curve (AUC) were lower, while the time at which the C max is observed (T max ) and the terminal elimination half‐life were longer compared to the reference product (RP) (Petrides et al , ).…”

“…In a phase I trial, the relative bioavailability compared to a reference product (RP) was 55% under fasting conditions and 60% under fed conditions (Petrides et al , ). As expected for a prolonged release formulation, the maximum concentration (C max ) and the area under the curve (AUC) were lower, while the time at which the C max is observed (T max ) and the terminal elimination half‐life were longer compared to the reference product (RP) (Petrides et al , ). The current randomized, double blind, multicentre, multinational trial aimed to compare the efficacy, safety and tolerability of A‐PR and the RP in anagrelide‐naïve and –experienced ET patients with an indication for cytoreductive treatment.…”