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Cladribine | CAS No: 4291-63-8 | GMP-certified suppliers
A medication that treats active hairy cell leukemia and serves as an alternative for chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, and cutaneous T-cell lymphoma.
Therapeutic categories
Primary indications
- For the treatment of active hairy cell leukemia (leukemic reticuloendotheliosis) as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms
- Also used as an alternative agent for the treatment of chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin's lymphoma, and cutaneous T-cell lymphoma
Product Snapshot
- Cladribine is available in injectable and oral formulations including intravenous, subcutaneous, and tablet forms
- It is primarily used for hematologic malignancies such as hairy cell leukemia, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, and cutaneous T-cell lymphoma
- Cladribine holds approvals or investigational status in key regulatory markets including the US, Canada, and the EU
Clinical Overview
Chemically, cladribine is classified as a purine 2'-deoxyribonucleoside, consisting of a purine base linked to a deoxyribose sugar lacking a hydroxyl group at the 2’ position. Structural modification by the substitution of a chlorine atom at position 2 of the purine ring confers resistance to enzymatic degradation by adenosine deaminase, extending its cytotoxic activity.
Pharmacodynamically, cladribine exerts antineoplastic and immunosuppressive effects by disrupting DNA synthesis and repair. It is phosphorylated intracellularly by deoxycytidine kinase into its active triphosphate form (CdATP), which accumulates preferentially in lymphocytes due to their enzymatic profile. CdATP incorporates into DNA, inducing strand breaks and inhibiting further synthesis and repair processes. Additionally, CdATP inhibits ribonucleotide reductase, resulting in imbalances in nucleotide pools and subsequent cytotoxicity. Unlike many antimetabolites, cladribine affects both resting and proliferating lymphocytes, with evidence of cell cycle arrest at the G1/S phase junction.
Key absorption, distribution, metabolism, and excretion (ADME) parameters include intracellular phosphorylation for activation, with metabolic resistance to adenosine deaminase degradation prolonging its half-life. The drug’s mechanisms contribute to myelosuppression, immunosuppression, and potential cardiotoxicity. Safety considerations highlight a narrow therapeutic index, with risks of hematologic toxicity, immunosuppression-related infections, and possible muscle toxicity.
Cladribine is classified under several drug categories including purine analogues and immunosuppressants and is recognized as an approved agent in relevant oncologic treatment protocols. Notable usage involves specialized hematologic oncology settings.
For pharmaceutical formulation and API sourcing, emphasis should be placed on stringent quality control due to the compound’s narrow therapeutic index and the complexity of synthesis. Sourcing compliance with regulatory guidelines, including verification of purity, stability, and absence of related impurities, is critical to ensure clinical safety and efficacy.
Identification & chemistry
| Generic name | Cladribine |
|---|---|
| Molecule type | Small molecule |
| CAS | 4291-63-8 |
| UNII | 47M74X9YT5 |
| DrugBank ID | DB00242 |
Pharmacology
| Summary | Cladribine is a synthetic purine nucleoside analog with cytotoxic and immunosuppressive effects, primarily targeting lymphocytes. It is phosphorylated intracellularly to cladribine triphosphate, which incorporates into DNA and inhibits DNA synthesis and repair, leading to DNA strand breaks and cell death. Additionally, cladribine interferes with ribonucleotide reductase activity, disrupting deoxynucleotide pools, and affects both resting and proliferating lymphocyte populations. |
|---|---|
| Mechanism of action | Cladribine is structurally related to fludarabine and pentostatin but has a different mechanism of action. Although the exact mechanism of action has not been fully determined, evidence shows that cladribine is phosphorylated by deoxycytidine kinase to the nucleotidecladribine triphosphate (CdATP; 2-chloro-2′-deoxyadenosine 5′-triphosphate), which accumulates and is incorporated into DNA in cells such as lymphocytes that contain high levels of deoxycytidine kinase and low levels of deoxynucleotidase, resulting in DNA strand breakage and inhibition of DNA synthesis and repair. High levels of CdATP also appear to inhibit ribonucleotide reductase, which leads to an imbalance in triphosphorylated deoxynucleotide (dNTP) pools and subsequent DNA strand breaks, inhibition of DNA synthesis and repair, nicotinamide adenine dinucleotide (NAD) and ATP depletion, and cell death. Unlike other antimetabolite drugs, cladribine has cytotoxic effects on resting as well as proliferating lymphocytes. However, it does cause cells to accumulate at the G1/S phase junction, suggesting that cytotoxicity is associated with events critical to cell entry into S phase. It also binds purine nucleoside phosphorylase (PNP), however no relationship between this binding and a mechanism of action has been established. |
| Pharmacodynamics | Cladribine is a synthetic purine nucleoside that acts as an antineoplastic agent with immunosuppressive effects. Cladribine differs structurally from deoxyadenosine only by the presence of a chlorine atom at position 2 of the purine ring, which results in resistance to enzymatic degradation by adenosine deaminase. Due to this resistance, cladribine exhibits a more prolonged cytotoxic effect than deoxyadenosine against resting and proliferating lymphocytes. Cladribine is one of a group of chemotherapy drugs known as the anti-metabolites. Anti-metabolites stop cells from making and repairing DNA, which are processes that are necessary for cancer cells to grow and multiply. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Ribonucleoside-diphosphate reductase large subunit | Humans | inhibitor |
| Ribonucleoside-diphosphate reductase subunit M2 | Humans | inhibitor |
| Ribonucleoside-diphosphate reductase subunit M2 B | Humans | inhibitor |
ADME / PK
| Absorption | Oral bioavailability is 34 to 48%. |
|---|---|
| Half-life | 5.4 hours |
| Protein binding | 20% |
| Metabolism | Metabolized in all cells with deoxycytidine kinase activity to 2-chloro-2'-deoxyadenosine-5'-triphosphate |
| Volume of distribution | * 4.5 ± 2.8 L/kg [patients with hematologic malignancies] * 9 L/kg |
| Clearance | * 978 +/- 422 mL/h/kg |
Formulation & handling
- Cladribine is available in both oral tablet and injectable formulations suitable for intravenous and subcutaneous administration.
- As a small molecule purine nucleoside analog, cladribine exhibits moderate water solubility and low lipophilicity (LogP -0.28), facilitating formulation in aqueous solutions.
- Avoid co-administration with echinacea due to potential impacts on immunosuppressive efficacy; no significant food sensitivity otherwise reported.
Regulatory status
| Lifecycle | The API is currently entering the post-patent expiry phase in the United States for key patents expiring in 2024, with additional patent protections extending through 2026 and a final patent lasting until 2038. Products containing the API are marketed in the US, Canada, and EU, reflecting a mature but evolving market landscape. |
|---|
| Markets | US, Canada, EU |
|---|
Supply Chain
| Supply chain summary | The manufacturing and supply landscape for cladribine involves multiple originator companies producing and packaging the API, primarily serving the US, Canadian, and EU markets. Branded products are established across these regions, with patents expiring between 2024 and 2026 indicating potential availability for generic competition in the near term. However, a later patent extending to 2038 suggests some formulations or uses remain under patent protection, potentially limiting generic entry for specific indications or product versions. |
|---|
Safety
| Toxicity | Symptoms of overdose include irreversible neurologic toxicity (paraparesis/quadriparesis), acute nephrotoxicity, and severe bone marrow suppression resulting in neutropenia, anemia and thrombocytopenia. |
|---|
- Handling requires appropriate protective measures to prevent exposure, as overdose may cause irreversible neurologic toxicity
- Avoid inhalation, ingestion, or skin contact due to potential acute nephrotoxicity
- Use in controlled environments due to risk of severe bone marrow suppression impacting neutrophil, erythrocyte, and platelet counts
Cladribine is a type of Antineoplastics
Antineoplastics are a crucial category of pharmaceutical active pharmaceutical ingredients (APIs) primarily used in the treatment of cancer. These powerful substances inhibit or destroy the growth of cancer cells, thus impeding the progression of malignancies.
Antineoplastics exert their therapeutic effects through various mechanisms. Some APIs interfere with DNA replication, inhibiting the division and proliferation of cancer cells. Others target specific proteins or enzymes involved in tumor growth, effectively blocking their function. Additionally, certain antineoplastic agents induce programmed cell death, known as apoptosis, in cancer cells.
These APIs find application in a wide range of cancer treatments, including chemotherapy, targeted therapy, immunotherapy, and hormone therapy. They are often administered in combination with other drugs to optimize therapeutic outcomes and minimize drug resistance.
Antineoplastics are typically synthesized through complex chemical processes, ensuring high purity and potency. Stringent quality control measures are implemented throughout manufacturing to meet regulatory standards and ensure patient safety.
Although antineoplastics offer significant benefits in treating cancer, they can also cause adverse effects due to their cytotoxic nature. Common side effects include bone marrow suppression, gastrointestinal disturbances, hair loss, and immune system suppression. Close monitoring and supportive care are essential to manage these side effects effectively.
In conclusion, antineoplastics are a vital category of pharmaceutical APIs used in the treatment of cancer. Through their diverse mechanisms of action, these compounds play a critical role in combating malignancies and improving patient outcomes.
Cladribine API manufacturers & distributors
Compare qualified Cladribine API suppliers worldwide. We currently have 5 companies offering Cladribine API, with manufacturing taking place in 4 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 |
|---|---|---|---|---|---|
| Cilag AG | Producer | Switzerland | Switzerland | CoA, USDMF | 5 products |
| Global Pharma Tek | Distributor | India | India | BSE/TSE, CoA, FDA, GMP, ISO9001, MSDS | 484 products |
| Reliable Biopharm | Producer | United States | United States | CoA, USDMF | 11 products |
| Sinoway industrial Co.,Lt... | Distributor | China | China | CoA, GMP, ISO9001, MSDS, USDMF | 762 products |
| Zhejiang Hisun Pharma | Producer | China | China | CoA, USDMF | 69 products |
When sending a request, specify which Cladribine API quality you need: for example EP (Ph. Eur.), USP, JP, BP, or another pharmacopoeial standard, as well as the required grade (base, salt, micronised, specific purity, etc.).
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