title: 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 Tmaxand T1/2were significantly shorter after the CARP compared with AER. Food had a significant impact on the PK of AER, increasing the Cmaxand AUCtwhile 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.
authors.affiliation: Hematology Oncology Center and Ludwig Maximilians University of Munich Medical School, Munich, Germany.
authors.forename: Petro E
authors.initials: PE
authors.lastname: Petrides
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Schoergenhofer
authors.affiliation: AOP Orphan Pharmaceuticals AG, Vienna, Austria.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Widmann
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Bernd
authors.initials: B
authors.lastname: Jilma
authors.affiliation: AOP Orphan Pharmaceuticals AG, Vienna, Austria.
authors.forename: Christoph S
authors.initials: CS
authors.lastname: Klade
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics; D005215:Fasting / Q000378:metabolism; D005260:Female; D005343:Fibrinolytic Agents / Q000097:blood / Q000493:pharmacokinetics*; D018565:Food-Drug Interactions; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D003692:Delayed-Action Preparations; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D011799:Quinazolines; C021139:anagrelide
keywords: anagrelide; bioavailability; drug delivery; extended release; healthy volunteers; pharmacokinetics; platelets