Medical Pharmacology Chapter 33-34: Anticancer Drugs
Purine Analogues: 6-Thiopurines:
Fludarabine (9-β-d-arabinosyl-2-fluoroadenine monophosphate, F-ara AMP, Fludara) is an antineoplastic drug used for treating CLL (chronic lymphocytic leukemia).6
Fludarabine is a monophosphate adenosine analog with the monophosphate form responsible for the aqueous solubility that allows IV administration.9
Fludarabine monophosphate is hydrolyzed to fludarabine in the bloodstream.
Fludarabine monophosphate exhibits both adenosine deaminase resistance and ready incorporation into DNA, resulting in chain termination.9
This agent exhibits anticancer activity also in the setting of: 6
Indolent non-Hodgkin's lymphoma,
Cutaneous T-cell lymphoma and
Fludarabine administration may be also associated with significant immunosuppression.1
Fludarabine is not effective for treating solid tumors.6
Fludarabine is related to the antiviral drug vidarabine (9-β-d-arabinofuranosyl-adenenine).1
Fludarabine phosphate differs from vidarabine in that it is fluorinated, phosphorylated, and deamination-resistant.1
Following IV infusion, fludarabine phosphate is rapidly dephosphorylated (in plasma) to the nucleoside, 9-β-d-arabinosyl-2-fluoroadenine (F-ara-A).9
F-ara-A by means of the equilibrative carrier ENT1 (a.k.a. hENT1) and then phosphorylated to F-ara-ATP, the active form.
Cytotoxicity requires fludarabine triphosphate (F-ara-ATP). F-ara-ATP is an inhibitor of several important enzymes central to DNA replication.
These enzymes include:
DNA primase, and
DNA ligase I.9,6
Following fludarabine incorporation into DNA, F-ara AMP causes DNA chain termination (3' end of DNA).
The loss of "clonogenicity" is linearly associated with the extent of fludarabine incorporation into DNA.
The 3'-terminal F-ara AMP, following incorporation, is not readily subject to excision repair and, as a result, initiates "programmed cell death" or apoptosis.9
F-ara ADP is an inhibitor of ribonucleotide reductase.
This effect decreases dATP levels and enhances incorporation of the inhibitor instead of normally occurring dAMP into DNA.9
In distinction from other antineoplastic antimetabolite agents, fludarabine is also active against nondividing cells.
Fludarabine's primary anticancer effects may be due to initiation of programmed cell death (apoptosis).
Activity against nondividing cells may provide a basis for understanding fludarabine activity in indolent lymphoproliferative disease exhibiting "low growth fractions".
Fudarabine incorporation into RNA results in inhibition of RNA function, processing and mRNA translation.1
Fludarabine phosphate may be administered orally and by the IV route of administration.
The monophosphate form is converted to fludarabine in the plasma.1,9
The dephosphorylating reaction (2-F-ara-A AMP to F-ara-A) is catalyzed by erythrocyte and endothelial cell 5' nucleotidase.1,9
Following oral administration maximal drug fludarabine in plasma is reached in about 1.5 hours.1
The oral bioavailability is about 50%-60% with the t1/2 plasma elimination is approximately 10 hours.1
Drug clearance appears stable with repeated doses in individuals.9
In circulating leukemic cells, peak F-ara ATP occurs in about four hours after IV fludarabine administration.9
F-ara ATP exibits an intracellular half-life of about 15 hours, long enough to explain effectiveness of a daily administration protocol.
Plasma concentrations of F-ara-A (9-beta-D-arabinofuranosyl-2-fluoroadenine) are reflected directly in intracellular F-ara ATP leukemic cells.9
Excretion of F-ara-A is mainly renal (urine) with about a 55% recovery.
No metabolites are detectable. Individuals with renal impairment when compared to patients with normal renal function exhibit decreasing clearance of 2-F-ara-A.
Dosage reduction in patients with impaired renal function have been recommended depending on, in part, the extent of renal dysfunction.9
Toxicity:9 (primary reference for this section: Hande KR Chabner BA Purine Analogs Chapter 10 in: Cancer Chemotherapy, Immunotherapy and Biotherapy Principles and Practice Chabner BA Longo DL, eds 6e Wolters Kluwer 2019.)
The major dose-limiting fludarabine toxicities include myelosuppression and complications, typically infectious, due to immunosuppression.9
Both oral and intravenous administration of fludarabine are comparable in their toxicity profiles.
Fludarabine administration may induce a reversible leukopenia and thrombocytopenia at various levels of severity.
Myelosuppression is more likely to occur in those cases in which fludarabine is combined with other anticancer drugs, including rituximab.
As many as 25% of patients receiving fludarabine may present with fever often not associated with infection although perhaps one-third of patients presenting with fever will have a documented infectious cause.
Immunosupressive activity of fludarabine is substantial as it inhibits signal transduction central to lymphocyte activation.9
Accordingly, fludarabine treatment may render a patient susceptible to opportunistic infection in accord with reduced T-lymphocyte subpopulations CD4 and CD8.
Immunosuppression-related lymphopenia may last more than one year.
Respiratory infectious complications are the most likely and the specific infections include: 9
Pneumocystis jiroveci (previously knows as Pneumocystis carinii)
Herpes Smplex Virus
Autoimmune hemolytic anemia may be observed following fludarabine due to suppression of T-reg lymphocytes.9
Hemolysis may also occur during treatment cycles, most likely during cycles 1 through 3.
A fatal complication in patients with CLL and indolent lymphoma treated with fludarabine is acute tumor lysis.
Numerous other toxicities have been reported such as mild nausea and vomiting, peripheral sensorimotor neuropathy, hepatocellular toxicity and rash.
Neurotoxicity may occur in about 16% of patients receiving fludarabine at higher doses,
This form presents as in irreversible neurotoxicity syndrome described as including cortical blindness, encepalopathy, optic neuritis, generalized seizures and coma.9
Lower doses of fludarabine, in terms of neurotoxicity, is more likely to cause a mild in reversible form.
In about 5%-10% of patients interstitial pneumonitis may occur and pulmonary toxicity more generally is associated with fever, cough, and hypoxia.
Late adverse effects of fludarabine therapy may include myelodysplasia and acute myelogenous leukemia (AML).9