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Clofarabine | CAS No: 123318-82-1 | GMP-certified suppliers
A medication that treats relapsed or refractory pediatric acute lymphoblastic leukemia, offering targeted antineoplastic benefits with critical importance on quality and supply consistency.
Therapeutic categories
Primary indications
- For the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphocytic (lymphoblastic) leukemia after at least two prior regimens
- It is designated as an orphan drug by the FDA for this use
Product Snapshot
- Clofarabine is an injectable small molecule formulation administered intravenously
- It is primarily indicated for the treatment of relapsed or refractory acute lymphoblastic leukemia in pediatric patients
- Clofarabine holds approval or investigational status in key regulatory markets including the US, Canada, and the EU
Clinical Overview
Pharmacologically, clofarabine is classified as a purine 2'-deoxyribonucleoside analogue, distinguished by the presence of chlorine on the purine ring and fluorine in the ribose moiety. Its cytotoxic activity arises from inhibition of nucleic acid synthesis, ultimately interfering with DNA and RNA replication required for cancer cell proliferation.
Mechanistically, clofarabine undergoes intracellular phosphorylation to its active 5'-triphosphate metabolite via deoxycytidine kinase followed by additional kinase-mediated phosphorylation steps. The active metabolite inhibits ribonucleotide reductase and competitively blocks DNA polymerases, resulting in depletion of deoxynucleotide triphosphates and termination of DNA chain elongation. Additionally, it impairs DNA repair by incorporation into DNA strands and disrupts mitochondrial membrane integrity, triggering release of pro-apoptotic factors such as cytochrome C and apoptosis-inducing factor. These mechanisms cumulatively induce programmed cell death in malignant cells.
Key ADME considerations include primary renal excretion and intracellular activation by nucleoside kinases. Clofarabine exhibits a narrow therapeutic index, necessitating careful dose management to mitigate toxicities such as myelosuppression and immunosuppression. Safety monitoring is emphasized due to risks of hematologic adverse effects and potential off-target impacts on normal proliferating cells.
From a procurement perspective, assurance of API quality through compliance with stringent regulatory standards and reliable supply chain management is critical. The drug’s narrow therapeutic index and complex metabolism highlight the importance of sourcing clofarabine with verified purity, consistent potency, and validated impurity profiles to support safe and effective pharmaceutical product formulation.
Identification & chemistry
| Generic name | Clofarabine |
|---|---|
| Molecule type | Small molecule |
| CAS | 123318-82-1 |
| UNII | 762RDY0Y2H |
| DrugBank ID | DB00631 |
Pharmacology
| Summary | Clofarabine is a purine nucleoside antimetabolite that targets DNA synthesis by inhibiting ribonucleotide reductase and competitively inhibiting DNA polymerases, resulting in termination of DNA chain elongation and impaired DNA repair. Its active triphosphate metabolite also disrupts mitochondrial membrane integrity, inducing apoptosis through release of pro-apoptotic factors. Clofarabine’s mechanism leads to depletion of deoxynucleotide pools and inhibition of nucleic acid synthesis, primarily affecting rapidly proliferating malignant cells. |
|---|---|
| Mechanism of action | Clofarabine is metabolized intracellularly to the active 5'-monophosphate metabolite by deoxycytidine kinase and 5'-triphosphate metabolite by mono- and di-phospho-kinases. This metabolite inhibits DNA synthesis through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair through competitive inhibition of DNA polymerases. This leads to the depletion of the intracellular deoxynucleotide triphosphate pool and the self-potentiation of clofarabine triphosphate incorporation into DNA, thereby intensifying the effectiveness of DNA synthesis inhibition. The affinity of clofarabine triphosphate for these enzymes is similar to or greater than that of deoxyadenosine triphosphate. In preclinical models, clofarabine has demonstrated the ability to inhibit DNA repair by incorporation into the DNA chain during the repair process. Clofarabine 5'-triphosphate also disrupts the integrity of mitochondrial membrane, leading to the release of the pro-apoptotic mitochondrial proteins, cytochrome C and apoptosis-inducing factor, leading to programmed cell death. |
| Pharmacodynamics | Clofarabine is a purine nucleoside antimetabolite that differs from other puring nucleoside analogs by the presence of a chlorine in the purine ring and a flourine in the ribose moiety. Clofarabine seems to interfere with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by clofarabine, other effects also occur. Clofarabine prevents cells from making DNA and RNA by interfering with the synthesis of nucleic acids, thus stopping the growth of cancer cells. |
Targets
| Target | Organism | Actions |
|---|---|---|
| DNA | Humans | other/unknown |
| DNA polymerase alpha catalytic subunit | Humans | inhibitor |
| Ribonucleoside-diphosphate reductase large subunit | Humans | inhibitor |
ADME / PK
| Half-life | The terminal half-life is estimated to be 5.2 hours. |
|---|---|
| Protein binding | 47% bound to plasma proteins, predominantly to albumin. |
| Metabolism | Clofarabine is sequentially metabolized intracellularly to the 5’-monophosphate metabolite by deoxycytidine kinase and mono- and di-phosphokinases to the active 5’-triphosphate metabolite. Clofarabine has high affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equal to or greater than that of the natural substrate, deoxycytidine. |
| Route of elimination | Based on 24-hour urine collections in the pediatric studies, 49 - 60% of the dose is excreted in the urine unchanged. |
| Volume of distribution | * 172 L/m2 |
| Clearance | * 28.8 L/h/m2 [Pediatric patients (2 - 19 years old) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) receiving 52 mg/m2 dose] |
Formulation & handling
- Clofarabine is administered exclusively via intravenous injection as a small molecule purine nucleoside analog.
- The API exhibits moderate water solubility, facilitating formulation into aqueous injectable solutions at typical concentrations around 1 mg/mL.
- Coadministration with echinacea may reduce immunosuppressive efficacy, warranting caution during concurrent use.
Regulatory status
| Lifecycle | The active pharmaceutical ingredient is currently marketed in the US, Canada, and EU, with patent protection expired in Canada since 2012 and in the US since 2018, indicating a mature market with potential availability of generic alternatives. |
|---|
| Markets | US, Canada, EU |
|---|
Supply Chain
| Supply chain summary | Clofarabine is primarily manufactured and packaged by a limited number of originator companies with a presence in the US, Canada, and EU markets. The product is branded consistently across these regions. Patent expirations in Canada (2012) and the United States (2018) indicate opportunities for existing or upcoming generic competition in these markets. |
|---|
Safety
| Toxicity | There were no known overdoses of clofarabine. The highest daily dose administered to a human to date (on a mg/m<sup>2</sup> basis) has been 70 mg/m<sup>2</sup>/day × 5 days (2 pediatric ALL patients). The toxicities included in these 2 patients included grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash. |
|---|
- Clofarabine exposure at high doses may cause hepatotoxicity, including severe hyperbilirubinemia
- Adverse effects observed at elevated doses include gastrointestinal symptoms such as vomiting and dermatologic reactions like maculopapular rash
- No documented cases of overdose have been reported in clinical settings to date
Clofarabine 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.
Clofarabine API manufacturers & distributors
Compare qualified Clofarabine API suppliers worldwide. We currently have 9 companies offering Clofarabine API, with manufacturing taking place in 3 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 |
|---|---|---|---|---|---|
| Biophore India | Producer | India | India | CoA, USDMF | 46 products |
| Emcure Pharma | Producer | India | India | CoA, USDMF | 80 products |
| Global Pharma Tek | Distributor | India | India | BSE/TSE, CoA, FDA, GMP, ISO9001, MSDS | 484 products |
| Janssen Pharma | Producer | Belgium | Netherlands | CoA, GMP | 63 products |
| MSN Labs. | Producer | India | India | CoA, GMP, USDMF, WC | 119 products |
| Shilpa Medicare Ltd | Producer | India | India | BSE/TSE, CoA, GMP, ISO9001, MSDS, USDMF, WC | 54 products |
| Sionc Pharma | Producer | India | India | CoA, WC | 10 products |
| Sun Pharma | Producer | India | India | CoA, USDMF | 219 products |
| Synbias Pharma | Producer | Switzerland | Switzerland | CoA, USDMF | 7 products |
When sending a request, specify which Clofarabine 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.).
Use the list above to find high-quality Clofarabine API suppliers. For example, you can select GMP, FDA or ISO certified suppliers. Visit our help page to learn more about sourcing APIs via Pharmaoffer.
