Fludarabine

Synonyms :
2-Fluoro-ara AMP, 2-Fluoroadenine arabinoside 5′-monophosphate, 2F-Ara-AMP, 9-beta-Arabinofuranosyl-2-fluoroadenine-5′-phosphate, 9-beta-D-Arabinofuranosyl-2-fluoroadenine 5′-(dihydrogen phosphate), 9-beta-D-Arabinofuranosyl-2-fluoroadenine 5′-monophosphate, FAMP, Fludara, Fludarabine 5′-monophosphate, Fludarabine monophosphate, Fludarabine phosphate

Status : approved

Category

Antineoplastic Agents

Therapeutic Classification

ANTIMETABOLITES

ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
ANTINEOPLASTIC AGENTS
ANTIMETABOLITES

Description

Fludarabine (marketed as fludarabine phosphate under the trade name Fludara) is a chemotherapy drug used in the treatment of hematological malignancies. [Wikipedia]

Used

For the treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating-agent containing regimen

Mechanism Of Action

Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted.

Dosage

Form Route Strength
Solution intravenous 25.0 mg
Tablet oral 10 mg
Injection, solution intravenous 25 mg/mL
Injection intravenous 25 mg/mL
Injection, powder, lyophilized, for solution intravenous 25 mg/mL
Injection, powder, lyophilized, for solution intravenous 50 mg/2mL
Solution intravenous 25 mg
Powder for solution intravenous 50 mg
Liquid intravenous 25 mg

Pharmacodynamics

Fludarabine is a chemotherapy drug used in the treatment of chronic lymphocytic leukemia. It acts at DNA polymerase alpha, ribonucleotide reductase and DNA primase, results in the inhibition of DNA synthesis, and destroys the cancer cells.

Absorption

Bioavailability is 55% following oral administration.

Half Life

20 hours

Protein Binding

19-29%

Clearance

* 117-145 mL/min [patients with B-cell CLL receiving IV administration of a single dose of 40 mg/m2]

Chemical Classification

This compound belongs to the class of organic compounds known as purine ribonucleoside monophosphates. These are nucleotides consisting of a purine base linked to a ribose to which one monophosphate group is attached.

Purine ribonucleoside monophosphates

Organic compounds

Nucleosides, nucleotides, and analogues

Purine nucleotides

Purine ribonucleotides

Salt : Fludarabine monophosphate

Chemical Name

2-Fluoro-ara AMP

Brands

name Dosage form Country
Aj-fludarabine solution Canada
Fludara tablet Canada
Fludara powder for solution Canada
Fludarabine injection, solution US
Fludarabine injection, powder, lyophilized, for solution US
Fludarabine Phosphate injection, powder, lyophilized, for solution US
Fludarabine Phosphate injection, powder, lyophilized, for solution US
Fludarabine Phosphate injection US
Fludarabine Phosphate injection, powder, lyophilized, for solution US
Fludarabine Phosphate injection US
Fludarabine Phosphate injection, solution US
Fludarabine Phosphate injection, solution US
Fludarabine Phosphate injection, powder, lyophilized, for solution US
Fludarabine Phosphate injection, solution US
Fludarabine Phosphate injection, powder, lyophilized, for solution US
Fludarabine Phosphate injection US
Fludarabine Phosphate for Injection solution Canada
Fludarabine Phosphate for Injection powder for solution Canada
Fludarabine Phosphate for Injection USP powder for solution Canada
Fludarabine Phosphate Injection solution Canada
Fludarabine Phosphate Injection liquid Canada
Fludarabine Phosphate Injection solution Canada
Fludarabine Phosphate Injection, USP solution Canada

Drug Drug Interactions

  •  Clozapine  : Myelosuppressive Agents may enhance the adverse/toxic effect of Clozapine. Specifically, the risk for agranulocytosis may be increased.
  •  Denosumab  : May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased.
  •  Imatinib  : May diminish the myelosuppressive effect of Fludarabine. Imatinib may decrease the serum concentration of Fludarabine. More specifically, imatinib may decrease the formation of fludarabine active metabolite F-ara-ATP
  •  Leflunomide  : Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased.
  •  Metamizole  : May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased
  •  Natalizumab  : Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased.
  •  Pentostatin  : Fludarabine may enhance the adverse/toxic effect of Pentostatin. Pentostatin may enhance the adverse/toxic effect of Fludarabine. Pulmonary toxicity is of specific concern.
  •  Pimecrolimus  : May enhance the adverse/toxic effect of Immunosuppressants.
  •  Roflumilast  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Sipuleucel-T  : Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T.
  •  Tofacitinib  : Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib.
  •  Trastuzumab  : May enhance the neutropenic effect of Immunosuppressants.

Food Interactions

  • Food slightly increases product bioavailability., Take without regard to meals.

Calculated Property

kind Value Source
logP -2.5 ALOGPS
logS -2.1 ALOGPS
Water Solubility 2.97e+00 g/l ALOGPS
logP -3.6 ChemAxon
IUPAC Name {[(2R,3S,4S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}phosphonic acid ChemAxon
Traditional IUPAC Name fludarabine ChemAxon
Molecular Weight 365.2117 ChemAxon
Monoisotopic Weight 365.053662512 ChemAxon
SMILES NC1=C2N=CN([C@@H]3O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]3O)C2=NC(F)=N1 ChemAxon
Molecular Formula C10H13FN5O7P ChemAxon
InChI InChI=1S/C10H13FN5O7P/c11-10-14-7(12)4-8(15-10)16(2-13-4)9-6(18)5(17)3(23-9)1-22-24(19,20)21/h2-3,5-6,9,17-18H,1H2,(H2,12,14,15)(H2,19,20,21)/t3-,5-,6+,9-/m1/s1 ChemAxon
InChIKey InChIKey=GIUYCYHIANZCFB-FJFJXFQQSA-N ChemAxon
Polar Surface Area (PSA) 186.07 ChemAxon
Refractivity 74.93 ChemAxon
Polarizability 28.88 ChemAxon
Rotatable Bond Count 4 ChemAxon
H Bond Acceptor Count 10 ChemAxon
H Bond Donor Count 5 ChemAxon
pKa (strongest acidic) 1.34 ChemAxon
pKa (strongest basic) 0.6 ChemAxon
Physiological Charge -2 ChemAxon
Number of Rings 3 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five 1 ChemAxon
Ghose Filter 0 ChemAxon
MDDR-Like Rule 0 ChemAxon

Affected organism

Humans and other mammals

Target within organism

  • Ribonucleoside-diphosphate reductase large subunit : in Human
  • DNA polymerase alpha catalytic subunit : in Human
  • DNA : in Human
  • Deoxycytidine kinase : in Human