Fludarabine
 | |
|---|---|
| Systematic (IUPAC) name | |
| [(2R,3R,4S,5R)-5-(6-amino-2-fluoro-purin-9-yl)- 3,4-dihydroxy-oxolan-2-yl]methoxyphosphonic acid | |
| Clinical data | |
| Trade names | Fludara |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a692003 |
| Pregnancy cat. | D |
| Legal status | Prescription Only (S4) (AU) POM (UK) |
| Routes | Intravenous, oral |
| Pharmacokinetic data | |
| Bioavailability | 55% |
| Protein binding | 19 to 29% |
| Half-life | 20 hours |
| Excretion | Renal |
| Identifiers | |
| CAS number | 75607-67-9  |
| ATC code | L01BB05 |
| PubChem | CID 657237 |
| DrugBank | DB01073 |
| ChemSpider | 571392 |
| UNII | P2K93U8740 |
| KEGG | D01907 |
| ChEBI | CHEBI:63599  |
| ChEMBL | CHEMBL1568 |
| Chemical data | |
| Formula | C10H13FN5O7P |
| Mol. mass | 365.212 g/mol |
| SMILES
| |
| |
| (what is this?) (verify) | |
Fludarabine or fludarabine phosphate (Fludara) is a chemotherapy drug used in the treatment of hematological malignancies (cancers of blood cells such as leukemias and lymphomas). It is a purine analog, which interferes with DNA synthesis.
Indications
Fludarabine is highly effective in the treatment of chronic lymphocytic leukemia, producing higher response rates than alkylating agents such as chlorambucil alone.[1] Fludarabine is used in various combinations with cyclophosphamide, mitoxantrone, dexamethasone and rituximab in the treatment of indolent non-Hodgkins lymphomas. As part of the FLAG regimen, fludarabine is used together with cytarabine and granulocyte colony-stimulating factor in the treatment of acute myeloid leukaemia. Because of its immunosuppressive effects, fludarabine is also used in some conditioning regimens prior to allogeneic stem cell transplant.
Pharmacology
Fludarabine is a purine analog, and can be given both orally and intravenously. Fludarabine inhibits DNA synthesis by interfering with ribonucleotide reductase and DNA polymerase. It is active against both dividing and resting cells. Being phosphorylated, fludarabine is ionized at physiologic pH and is effectually trapped in blood. This provides some level of specificity for blood cells, both cancerous and healthy.
Side effects
Fludarabine is associated with profound lymphopenia, and as a consequence, increases the risk of opportunistic infections significantly. Patients who have been treated with fludarabine will usually be asked to take co-trimoxazole or to use monthly nebulised pentamidine to prevent Pneumocystis jiroveci pneumonia. The profound lymphopenia caused by fludarabine renders patients susceptible to transfusion-associated graft versus host disease, a fatal complication of blood transfusion. For this reason, all patients who have ever received fludarabine should only be given irradiated blood components.
Fludarabine causes anemia, thrombocytopenia and neutropenia, requiring regular blood count monitoring. Some patients require blood and platelet transfusion, or G-CSF injections to boost neutrophil counts.
Fludarabine is associated with the development of severe autoimmune hemolytic anemia in a proportion of patients.[2]
Difficulties are often encountered when harvesting peripheral blood stem cells from patients previously treated with fludarabine.[3]
History
Fludarabine was produced by John Montgomery and Kathleen Hewson of the Southern Research Institute in 1968.[4] Their previous work involved 2-fluoroadenosine, which was unsafe for use in humans; the change to this arabinose analogue was inspired by the success of vidarabine.[4]
References
- ↑ Rai KR et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 2000;343:1750-7. doi:10.1056/NEJM200012143432402 PMID 11114313
- ↑ Gonzalez H et al. Severe autoimmune hemolytic anemia in eight patients treated with fludarabine. Hematol Cell Ther. 1998;40:113-8. PMID 9698219
- ↑ Tournilhac O et al. Impact of frontline fludarabine and cyclophosphamide combined treatment on peripheral blood stem cell mobilization in B-cell chronic lymphocytic leukemia. Blood 2004;103:363-5. PMID 12969985
- ↑ 4.0 4.1 Sneader, Walter (2005). Drug discovery: a history. New York: Wiley. p. 258. ISBN 0-471-89979-8.