Chemical formula: C₁₀H₁₃FN₅O₇P Molecular mass: 285.235 g/mol PubChem compound: 657237
Fludarabine is a water-soluble fluorinated nucleotide analogue of the antiviral agent vidarabine 9-β-D-arabinofuranosyladenine (ara-A) that is relatively resistant to deamination by adenosine deaminase.
Fludarabine phosphate is rapidly dephosphorylated to 2F-ara-A which is taken up by cells and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2F-ara-ATP. This metabolite has been shown to inhibit ribonucleotide reductase, DNA polymerase α/δ and ε, DNA primase and DNA ligase thereby inhibiting DNA synthesis. Furthermore, partial inhibition of RNA polymerase II and consequent reduction in protein synthesis occur.
While some aspects of the mechanism of action of 2F-ara-ATP are as yet unclear, it is assumed that effects on DNA, RNA and protein synthesis all contribute to inhibition of cell growth with inhibition of DNA synthesis being the dominant factor. In addition, in vitro studies have shown that exposure of CLL lymphocytes to 2F-ara-A triggers extensive DNA fragmentation and cell death characteristic of apoptosis.
The pharmacokinetics of fludarabine (2F-ara-A) have been studied after intravenous administration by rapid bolus injection and short-term infusion as well as following continuous infusion and after peroral dosing of fludarabine phosphate (2F-ara-AMP).
No clear correlation was found between 2F-ara-A pharmacokinetics and treatment efficacy in cancer patients.
However, occurrence of neutropenia and haematocrit changes indicated that the cytotoxicity of fludarabine phosphate depresses the haematopoiesis in a dose dependent manner.
2F-ara-AMP is a water-soluble prodrug of fludarabine (2F-ara-A), which is rapidly and quantitatively dephosphorylated in the human organism to the nucleoside fludarabine (2F-ara-A).
Another metabolite, 2F-ara-hypoxanthine, which represents the major metabolite in the dog, was observed in humans only to a minor extent.
After single dose infusion of 25 mg 2F-ara-AMP per m² to CLL patients for 30 minutes 2F-ara-A reached mean maximum concentrations in the plasma of 3.5-3.7 µM at the end of the infusion. Corresponding 2F-ara-A levels after the fifth dose showed a moderate accumulation with mean maximum levels of 4.4-4.8 µM at the end of infusion. During a 5-day treatment schedule 2F-ara-A plasma trough levels increased by a factor of about 2. An accumulation of 2F-ara-A over several treatment cycles can be excluded.
Postmaximum levels decayed in three disposition phases with an initial half-life of approximately 5 minutes, an intermediate half-life of 1-2 hours and a terminal half-life of approximately 20 hours.
An interstudy comparison of 2F-ara-A pharmacokinetics resulted in a mean total plasma clearance (CL) of 79 ± 40 ml/min/m² (2.2 ± 1.2 ml/min/kg) and a mean volume of distribution (Vss) of 83 ± 55 l/m² (2.4 ± 1.6 l/kg). Data showed a high interindividual variability. After intravenous and peroral administration of fludarabine phosphate, plasma levels of 2F-ara-A and areas under the plasma level time curves increased linearly with the dose, whereas half-lives, plasma clearance and volumes of distribution remained constant independent of the dose indicating a dose linear behaviour.
After peroral fludarabine phosphate doses, maximum 2F-ara-A plasma levels reached approximately 20-30% of corresponding intravenous levels at the end of infusion and occurred 1–2 hours postdose. The mean systemic 2F-ara-A availability was in the range of 50-65% following single and repeated doses and was similar after ingestion of a solution or immediate release tablet formulation. After peroral dose of 2F-ara-AMP with concomitant food intake a slight increase (<10%) of systemic availability (AUC), a slight decrease of maximum plasma levels (Cmax) of 2F-ara-A and a delayed time of occurrence of Cmax was observed; terminal half-lives were unaffected.
2F-ara-A elimination is largely by renal excretion. 40 to 60 % of the administered intravenous dose was excreted in the urine. Mass balance studies in laboratory animals with ³H-2F-ara-AMP showed a complete recovery of radio-labelled substances in the urine.
Individuals with impaired renal function exhibited a reduced total body clearance, indicating the need for a dose reduction. In vitro investigations with human plasma proteins revealed no pronounced tendency of 2F-ara-A protein binding.
2F-ara-A is actively transported into leukaemic cells, whereupon it is rephosphorylated to the monophosphate and subsequently to the di- and triphosphate. The triphosphate 2F-ara-ATP is the major intracellular metabolite and the only metabolite known to have cytotoxic activity. Maximum 2F-ara-ATP levels in leukaemic lymphocytes of CLL patients were observed at a median of 4 hours and exhibited a considerable variation with a median peak concentration of approximately 20 µM. 2F-ara-ATP levels in leukaemic cells were always considerably higher than maximum 2F-ara-A levels in the plasma indicating an accumulation at the target sites. In-vitro incubation of leukaemic lymphocytes showed a linear relationship between extracellular 2F-ara-A exposure (product of 2F-ara-A concentration and duration of incubation) and intracellular 2F-ara-ATP enrichment. 2F-ara-ATP elimination from target cells showed median half-life values of 15 and 23 hours.
In acute toxicity studies, single doses of fludarabine produced severe intoxication symptoms or death at dosages about two orders of magnitude above the therapeutic dose. As expected for a cytotoxic compound, the bone marrow, lymphoid organs, gastrointestinal mucosa, kidneys and male gonads were affected. In patients, severe side effects were observed closer to the recommended therapeutic dose (factor 3 to 4) and included severe neurotoxicity partly with lethal outcome.
Systemic toxicity studies following repeated administration of fludarabine showed also the expected effects on rapidly proliferating tissues above a threshold dose. The severity of morphological manifestations increased with dose levels and duration of dosing and the observed changes were generally considered to be reversible. In principle, the available experience from the therapeutic use of fludarabine points to a comparable toxicological profile in humans, although additional undesirable effects such as neurotoxicity were observed in patients.
The results from intravenous animal embryotoxicity studies in rats and rabbits indicated an embryolethal and teratogenic potential of fludarabine as manifested in skeletal malformations, foetal weight loss and post implantation loss. In view of the small safety margin between the teratogenic doses in animals and the human therapeutic dose as well as in analogy to other antimetabolites which are assumed to interfere with the process of differentiation, the therapeutic use of fludarabine is associated with a relevant risk of teratogenic effects in humans.
Fludarabine has been shown to cause DNA-damage in a sister chromatid exchange test, to induce chromosomal aberrations in an in vitro cytogenetic assay and to increase the rate of micronuclei in the mouse micronucleus test in vivo, but was negative in gene mutation assays and in the dominant lethal test in male mice. Thus, the mutagenic potential was demosnstrated in somatic cells but could not be shown in germ cells.
The known activity of fludarabine at the DNA-level and the mutagenicity test results form the basis for the suspicion of a tumorigenic potential. No animal studies which directly address the question of tumorigenicity have been conducted, because the suspicion of an increased risk of second tumours due to fludarabine therapy can exclusively be verified by epidemiological data.
According to the results from animal experiments following intravenous administration of fludarabine, no remarkable local irritation has to be expected at the injection site. Even in case of misplaced injections, no relevant local irritation was observed after paravenous, intraarterial, and intramuscular administration of an aqueous solution containing 7.5 mg fludarabine/ml.
The similarity in nature of the observed lesions in the gastrointestinal tract after intravenous or intragastric dosing in animal experiments supports the assumption that the fludarabine induced enteritis is a systemic effect.
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