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Anagrelide | CAS No: 68475-42-3 | GMP-certified suppliers
A medication that reduces elevated platelet counts in thrombocythemia secondary to malignant neoplasms, lowering thrombosis risk and alleviating thrombo-hemorrhagic symptoms.
Therapeutic categories
Primary indications
- Anagrelide is indicated for the treatment of thrombocythemia, secondary to malignant neoplasms, to reduce platelet count and the associated risk of thrombosis
- It is also beneficial in the amelioration of thrombocythemia symptoms including thrombo-hemorrhagic events
Product Snapshot
- Anagrelide is an oral small molecule available in capsule and tablet formulations
- It is primarily used to reduce platelet count in thrombocythemia secondary to malignant neoplasms and to manage related thrombo-hemorrhagic symptoms
- Anagrelide is approved for use in key regulatory markets including the US, Canada, and the EU
Clinical Overview
Structurally, anagrelide belongs to the quinazoline class of compounds, characterized by a fused benzene and pyrimidine ring system. Pharmacodynamically, it acts by suppressing transcription factors essential for megakaryocyte maturation, the bone marrow cells responsible for platelet production. This results in a gradual reduction of peripheral platelet counts, typically observable after 7 to 14 days of therapy. Due to its relatively short systemic residence time, dosing is administered two to four times daily, with cautious titration not exceeding an increase of 0.5 mg per week to mitigate adverse effects.
The precise mechanism by which anagrelide decreases platelet count remains incompletely defined but involves dose-dependent inhibition of megakaryocyte maturation. The drug disrupts the post-mitotic development of megakaryocytes, decreasing their size and DNA content (ploidy), potentially through indirect downregulation of key transcription factors such as GATA-1 and FOG-1. Anagrelide is also recognized as a phosphodiesterase 3A (PDE3A) inhibitor; however, its platelet-lowering action is distinct from PDE3 inhibition, which is observed only at doses higher than those used therapeutically for thrombocythemia. PDE3A inhibition may induce apoptosis in certain cancer cells, suggesting additional investigational applications.
Key pharmacokinetic parameters include oral bioavailability with frequent dosing schedules required due to limited half-life. Anagrelide undergoes metabolism involving cytochrome P450 CYP1A2 enzymes and is classified as a weak CYP1A2 inhibitor and substrate. It is noted as a narrow therapeutic index drug with a known risk for QTc interval prolongation, necessitating cardiac monitoring during treatment.
Safety considerations include potential impairment of female fertility, as indicated by animal studies; thus, women of reproductive age should be counselled regarding reproductive risks prior to initiation. Adverse cardiovascular effects such as tachycardia are reported, consistent with its pharmacological profile.
Clinically, anagrelide has been approved since the late 1990s and remains a relevant option for thrombocythemia management, sometimes preferred due to tolerability compared to agents like busulfan and hydroxyurea.
When sourcing anagrelide API, attention to strict compliance with pharmacopoeial standards is essential, given the compound’s narrow therapeutic index and potential for QTc prolongation. Control over impurity profiles, polymorphic form, and residual solvents should be rigorously monitored. Furthermore, reliable supply chains with demonstrated batch-to-batch consistency and stability data are critical to support formulation and regulatory requirements in global markets.
Identification & chemistry
| Generic name | Anagrelide |
|---|---|
| Molecule type | Small molecule |
| CAS | 68475-42-3 |
| UNII | K9X45X0051 |
| DrugBank ID | DB00261 |
Pharmacology
| Summary | Anagrelide is indicated for thrombocythemia and functions primarily by suppressing megakaryocyte maturation, thereby reducing platelet production. Its mechanism involves modulation of transcription factors essential for megakaryocytopoiesis, such as GATA-1 and FOG-1. While anagrelide inhibits phosphodiesterase 3A (PDE3A), its platelet-lowering effect appears independent of PDE3A inhibition. |
|---|---|
| Mechanism of action | The exact mechanism by which anagrelide lowers platelet count is unclear. Evidence from human trials suggests a dose-related suppression of megakaryocyte maturation, the cells responsible for platelet production - blood drawn from patients receiving anagrelide showed a disruption to the post-mitotic phase of megakaryocyte development and a subsequent reduction in their size and ploidy. This may be achieved via indirect suppression of certain transcription factors required for megakaryocytopoeisis, including GATA-1 and FOG-1. Anagrelide is a known inhibitor of phosphodiesterase 3A (PDE3A), although its platelet-lowering effects appear unrelated to this inhibition. While PDE3 inhibitors, as a class, can inhibit platelet aggregation, this effect is only seen at higher anagrelide doses (i.e. greater than those required to reduce platelet count). Modulation of PDE3A has been implicated in causing cell cycle arrest and apoptosis in cancer cells expressing both PDE3A and SLFN12, and may be of value in the treatment of gastrointestinal stromal tumours. |
| Pharmacodynamics | Anagrelide decreases platelet counts by suppressing transcription factors necessary for the synthesis and maturation of platelet-producing cells. The drug itself appears to have a relatively short residence time in the body necessitating twice or four times daily dosing. However, given that the pharmacological effect of anagrelide therapy is reliant on a gradual suppression of platelet-producing cells, it may take 7 to 14 days for its administration to be reflected in reduced platelet counts - for this reason any changes to anagrelide doses should not exceed 0.5 mg/day in any one week. Evidence from animal studies suggests anagrelide may impair female fertility. Female patients of reproductive age should be advised of the potential for adverse effects on fertility prior to initiating therapy. |
Targets
| Target | Organism | Actions |
|---|---|---|
| cGMP-inhibited 3',5'-cyclic phosphodiesterase A | Humans | inhibitor |
ADME / PK
| Absorption | Following oral administration, the bioavailability of anagrelide is approximately 70%. Given on an empty stomach, the C<sub>max</sub> is reached within 1 hour (T<sub>max</sub>) of administration. Co-administration with food slightly lowers the C<sub>max</sub> and increases the AUC, but not to a clinically significant extent. |
|---|---|
| Half-life | The t<sub>1/2</sub> of anagrelide and its active metabolite, 3-hydroxy anagrelide, are approximately 1.5 hours and 2.5 hours, respectively. |
| Metabolism | Anagrelide is extensively metabolized, primarily in the liver by cytochrome P450 1A2 (CYP1A2), into two major metabolites: 6,7-dichloro-3-hydroxy-1,5 dihydro-imidazo[2,1-b]quinazolin-2-one (3-hydroxy anagrelide) and 2-amino-5,6-dichloro-3,4,-dihydroquinazoline (RL603). The 3-hydroxy metabolite is considered pharmacologically active and carries a similar potency and efficacy in regards to its platelet-lowering effects, but inhibits PDE3 with a potency 40x greater than that of the parent drug. |
| Route of elimination | Following metabolism, urinary excretion of metabolites appears to be the primary means of anagrelide elimination. Less than 1% of an administered dose is recovered in the urine as unchanged parent drug, while approximately 3% and 16-20% of the administered dose is recovered as 3-hydroxy anagrelide and RL603, respectively. |
Formulation & handling
- Anagrelide is a small molecule intended for oral administration in capsule or tablet form.
- The compound belongs to the quinazoline class and exhibits moderate water solubility and lipophilicity (LogP 1.94).
- It can be taken with or without food, as food has minimal impact on its pharmacokinetics.
Regulatory status
| Lifecycle | The active pharmaceutical ingredient (API) is patented until 2027, with primary products marketed in the US, Canada, and EU regions. Post-patent expiry, the API is expected to transition into the generic market, reflecting increased competition and market maturity. |
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| Markets | US, Canada, EU |
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Supply Chain
| Supply chain summary | Anagrelide's manufacturing landscape includes multiple originator and generic suppliers, with Shire Development Inc. as a key originator alongside several large generic manufacturers such as Sandoz and Mylan. The branded products, including Agrylin, have a global presence across the US, Canada, and EU markets. Patent expiration has led to established generic competition, reflected by numerous manufacturers and packagers active in these regions. |
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Safety
| Toxicity | The oral LD<sub>50</sub> of anagrelide as reported in rats and mice is >1500mg/kg and >2500mg/kg, respectively. Symptoms of overdose may include hypotension, sinus tachycardia, and vomiting. As the therapeutic effect of anagrelide (i.e. platelet reduction) is dose-related, significant thrombocytopenia is expected in instances of overdose. Treatment of overdose should involve careful monitoring of platelet counts and complications such as bleeding. Employ symptomatic and supportive measures if clinically indicated. |
|---|
- Anagrelide exhibits low acute oral toxicity with LD50 values exceeding 1500 mg/kg in rats and 2500 mg/kg in mice
- Overdose may induce hypotension, sinus tachycardia, vomiting, and dose-dependent thrombocytopenia
- Handling protocols should include monitoring for hematologic abnormalities and support for cardiovascular symptoms in case of exposure
Anagrelide is a type of Platelet Aggregation Inhibitors
Platelet Aggregation Inhibitors are a crucial category of pharmaceutical Active Pharmaceutical Ingredients (APIs) used in the field of cardiology and thrombosis management. These inhibitors play a vital role in preventing platelet aggregation, a process responsible for the formation of blood clots. By inhibiting platelet aggregation, these APIs reduce the risk of arterial thrombosis, which can lead to severe cardiovascular events like heart attacks and strokes.
Platelet Aggregation Inhibitors primarily work by targeting specific receptors on platelet cells, thereby impeding their activation and subsequent aggregation. The most commonly utilized APIs in this category include acetylsalicylic acid (aspirin), clopidogrel, ticagrelor, and prasugrel. These drugs are available in various forms, such as tablets, capsules, and intravenous formulations, allowing flexibility in their administration.
The effectiveness of Platelet Aggregation Inhibitors lies in their ability to prevent platelets from adhering to each other and forming clots within blood vessels. This property is especially crucial in patients with a high risk of cardiovascular events, such as those with a history of heart disease, diabetes, or peripheral artery disease.
While Platelet Aggregation Inhibitors are generally safe and effective, they can also carry potential side effects, including bleeding complications. Therefore, their administration requires careful consideration of individual patient characteristics and risk factors.
In conclusion, Platelet Aggregation Inhibitors represent a significant category of pharmaceutical APIs used for the prevention of platelet aggregation and subsequent blood clot formation. By inhibiting this process, they contribute to the management and reduction of cardiovascular events, offering critical benefits to patients at risk.
Anagrelide API manufacturers & distributors
Compare qualified Anagrelide API suppliers worldwide. We currently have 4 companies offering Anagrelide API, with manufacturing taking place in 2 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| Chemisch-pharmazeutisches... | Producer | Germany | Germany | CoA, EDMF/ASMF, FDA, GMP, MSDS | 7 products |
| Cipla | Producer | India | India | CoA, GMP, USDMF, WC | 164 products |
| Global Pharma Tek | Distributor | India | India | BSE/TSE, CoA, FDA, GMP, ISO9001, MSDS | 484 products |
| Torrent Pharma | Producer | India | India | CoA, USDMF | 34 products |
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