Agrylin - General Information
Agrylin is a drug used for the treatment of essential thrombocytosis (ET; essential thrombocythemia). It also has been used in the treatment of chronic myeloid leukemia. [Wikipedia]
Pharmacology of Agrylin
Agrylin is a drug used for the treatment of essential thrombocytosis (ET; essential thrombocythemia). It works by inhibiting the maturation of megakaryocytes into platelets. The exact mechanism of action is unclear, although it is known to be a potent (IC50 = 36nM) inhibitor of phosphodiesterase-III.
Agrylin for patients
Anagrelide should be used with caution in patients with known or suspected heart disease, and only if the potential benefits of therapy outweigh the potential risks. Because of the positive inotropic effects and side-effects of anagrelide, a pre-treatment cardiovascular examination is recommended along with careful monitoring during treatment. In humans, therapeutic doses of anagrelide may cause cardiovascular effects, including vasodilation, tachycardia, palpitations, and congestive heart failure.
Exposure to anagrelide is increased 8-fold in patients with moderate hepatic impairment. Use of anagrelide in patients with severe hepatic impairment has not been studied. The potential risks and benefits of anagrelide therapy in a patient with mild and moderate impairment of hepatic function should be assessed before treatment is commenced. In patients with moderate hepatic impairment, dose reduction is required and patients should be carefully monitored for cardiovascular effects.
Limited PK and/or PD studies investigating possible interactions between anagrelide and other medicinal products have been conducted. In vivo interaction studies in humans have demonstrated that digoxin and warfarin do not affect the PK properties of anagrelide, nor does anagrelide affect the PK properties of digoxin or warfarin.
Although additional drug interaction studies have not been conducted, the most common medications used concomitantly with anagrelide in clinical trials were aspirin, acetaminophen, furosemide, iron, ranitidine, hydroxyurea, and allopurinol. There is no clinical evidence to suggest that anagrelide interacts with any of these compounds.
An in vivo interaction study in humans demonstrated that a single 1mg dose of anagrelide administered concomitantly with a single 900 mg dose of aspirin was generally well tolerated. There was no effect on bleeding time, PT or aPTT. No clinically relevant pharmacokinetic interactions between anagrelide and acetylsalicylic acid were observed. In that same study, aspirin alone produced a marked inhibition in platelet aggregation ex vivo. Anagrelide alone had no effect on platelet aggregation, but did slightly enhance the inhibition of platelet aggregation by aspirin.
Anagrelide is metabolized at least in part by CYP1A2. It is known that CYP1A2 is inhibited by several medicinal products, including fluvoxamine, and such medicinal products could theoretically adversely influence the clearance of anagrelide. Anagrelide demonstrates some limited inhibitory activity towards CYP1A2 which may present a theoretical potential for interaction with other coadministered medicinal products sharing that clearance mechanism e.g. theophylline.
Anagrelide is an inhibitor of cyclic AMP PDE III. The effects of medicinal products with similar properties such as inotropes milrinone, enoximone, amrinone, olprinone and cilostazol may be exacerbated by anagrelide.
There is a single case report, which suggests that sucralfate may interfere with anagrelide absorption.
Food has no clinically significant effect on the bioavailability of anagrelide.
Anagrelide is contraindicated in patients with severe hepatic impairment. Exposure to anagrelide is increased 8-fold in patients with moderate hepatic impairment. Use of anagrelide in patients with severe hepatic impairment has not been studied.
Additional information about Agrylin
Agrylin Indication: For the treatment of patients with thrombocythemia, secondary to myeloproliferative disorders, to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms including thrombo-hemorrhagic events.
Mechanism Of Action: The mechanism by which anagrelide reduces blood platelet count is still under investigation. Studies in patients support a hypothesis of dose-related reduction in platelet production resulting from a decrease in megakaryocyte hypermaturation. In blood withdrawn from normal volunteers treated with anagrelide, a disruption was found in the postmitotic phase of megakaryocyte development and a reduction in megakaryocyte size and ploidy. At therapeutic doses, anagrelide does not produce significant changes in white cell counts or coagulation parameters, and may have a small, but clinically insignificant effect on red cell parameters. Agrylin inhibits cyclic AMP phosphodiesterase III (PDEIII). PDEIII inhibitors can also inhibit platelet aggregation. However, significant inhibition of platelet aggregation is observed only at doses of anagrelide higher than those required to reduce platelet count.
Drug Interactions: Not Available
Food Interactions: Take without regard to meals.
Food appears to reduce the area under the curve by 13.8%, without clinical consequence.
Generic Name: Anagrelide
Synonyms: Anagrelide HCL; Anagrelide Hydrochloride; BL-4162A
Drug Category: Fibrinolytic Agents; Platelet Aggregation Inhibitors; Antithrombotic Agents
Drug Type: Small Molecule; Approved
Other Brand Names containing Anagrelide: Agrylin; Xagrid;
Absorption: Not Available
Toxicity (Overdose): There are no reports of overdosage with anagrelide, however thrombocytopenia, which can potentially cause bleeding, is expected from overdosage. Single oral doses of anagrelide at 2,500, 1,500 and 200 mg/kg in mice, rats and monkeys, respectively, were not lethal. Symptoms of acute toxicity were: decreased motor activity in mice and rats and softened stools and decreased appetite in monkeys.
Protein Binding: Not Available
Biotransformation: Extensive, with < 1% recovered unchanged in the urine. Metabolized primarily in the liver by cytochrome P450 1A2 (CYP1A2). Recently, it was found that anagrelide is bio-transformed in humans into two major metabolites (6,7-dichloro-3-hydroxy-1,5 dihydro-imidazo[2,1-b]quinazolin-2-one (BCH24426) and 2-amino-5,6-dichloro-3,4,-dihydroquinazoline (RL603). Whether these metabolites have biological activities that may underlie the mode of action of the parent drug is presently unclear.
Half Life: At fasting and at a dose of 0.5 mg of anagrelide, the plasma half-life is 1.3 hours.
Dosage Forms of Agrylin: Capsule Oral
Chemical IUPAC Name: 6,7-dichloro-5,10-dihydro-3H-imidazo[2,1-b]quinazolin-2-one
Chemical Formula: C10H7Cl2N3O
Anagrelide on Wikipedia: http://en.wikipedia.org/wiki/Anagrelide
Organisms Affected: Humans and other mammals