Fludarabine

Abstract

Fludarabine is a fluorinated purine analogue with antineoplastic activity in lymphoproliferative malignancies. Noncomparative studies have shown response rates in patients with chronic lymphocytic leukaemia (CLL) that appear to be at least equivalent to those achieved with conventional therapy. Prolymphocytic leukaemia, a form of CLL which is often resistant to conventional chemotherapy, has also responded to treatment with fludarabine. Fludarabine combined with prednisone has also induced good response rates in patients with CLL but the limited data suggest that this does not offer an advantage over fludarabine alone. Several clinical trials have demonstrated a good cytoreductive response in patients with advanced, low grade non-Hodgkin’s lymphoma, particularly that of follicular histology. Preliminary evidence indicates fludarabine in combination with cytarabine has therapeutic activity as salvage therapy in patients with acute leukaemia. Myelosuppression has been the major dose-limiting adverse effect reported in clinical trials of fludarabine. A reduction in CD4+ cell count may be associated with the increased incidence of fever and opportunistic infections in fludarabine recipients. Nausea and vomiting have also been commonly reported, but these are generally mild to moderate in severity. Reversible neurotoxicity has also been occasionally reported. Thus, fludarabine appears to offer a viable alternative to currently used treatments in CLL and low grade non-Hodgkin’s lymphoma. Other potential areas of use for fludarabine include acute leukaemias, Waidenstrom’s macroglobulinaemia and mycosis fungoides. However, trials of fludarabine in comparison with currently used therapies and also in combination with other antineoplastic agents are required to fully define its role in the treatment of lymphoid malignancies. In addition, because relapse in these diseases is common, long term trials assessing improvement in survival duration and quality of life would be of value. Fludarabine, a purine analogue, has demonstrated activity in culture and/or in murine tumour models against a number of human tumour types including non-Hodgkin’s lymphoma, leukaemia, breast cancer, non-small cell lung cancer and ovarian cancer. In patients with nonhaematological malignancies receiving fludarabine, T cell counts were decreased to a greater extent than were B cell counts. Fludarabine monophosphate is dephosphorylated to the metabolite 9-β-arabinofuranosyl-2-fluoroadenine (F-Ara-A) within 5 minutes of intravenous infusion. F-Ara-A is then transported into the cell where it is converted to its active form, F-Ara-A-triphosphate (F-Ara-ATP). Termination of DNA or RNA synthesis by incorporation of F-Ara-ATP into the elongating chain is thought to contribute to the mechanism of action of fludarabine. Additionally, DNA and RNA polymerase, DNA primase, DNA ligase and ribonucleotide reductase enzyme activity are inhibited by fludarabine, while deoxycytidine kinase activity is enhanced. Fludarabine appears to enhance the activity of a number of antitumour agents in vitro. Increased cell death was noted when fludarabine was combined with gallium nitrate, cytarabine (ARA-C), mitoxantrone, or cytarabine plus cisplatin. Concentrations of cytarabine triphosphate, the cytotoxic metabolite of cytarabine, were increased by pre-exposure to fludarabine both in vitro and in vivo. Dose- and schedule-dependent radiosensitisation was also noted with fludarabine in in vivo models. Following intravenous administration fludarabine is rapidly dephosphorylated to F-Ara-A; peak concentrations of F-Ara-A were observed at the first sampling time in all patients evaluated and it is the pharmacokinetic profile of this compound that has been determined. Volumes of distribution (44.2 to 96.2 vs 10.8 L/m²) and plasma clearances (4.1 and 9.1 vs 0.7 L/h/m²) calculated in adults were much larger than respective values determined in children. Differences in pharmacokinetic handling of the drug between adults and children, and use of different dosage regimens and/or methods to determine pharmacokinetic parameters are possible explanations for this discrepancy. Elimination kinetics have most often been described as biphasic with a distribution phase half-life of 0.9 to 1.7 hours and an elimination phase half-life of 6.9 to 12.4 hours. Using a fluorescence assay with a sensitivity limit lower than the more commonly used ultraviolet detection method, a terminal elimination half-life of 33.5 hours was noted. In 2 studies, an initial rapid distribution phase with a half-life of 5 and 9 minutes, respectively, was also found. A statistically significant relationship has been found between renal function parameters and the total body clearance of fludarabine, indicating a major role for renal mechanisms in its elimination. Increased serum creatinine and blood urea nitrogen levels have both been significantly correlated with decreased F-Ara-A elimination. Fludarabine-associated neutropenia appears to be more severe in patients with creatinine clearance <3 L/h (50 ml/min). Preliminary testing of an oral form of the drug indicates bioavailability of about 70%. F-Ara-A reached peak plasma concentrations following an oral dose (unspecified) in approximately 1.5 hours. Noncomparative studies have demonstrated objective response rates of 12 to 57% in patients with chronic lymphocytic leukaemia (CLL) receiving fludarabine as salvage therapy, and up to 86% in previously untreated patients. These are at least as high as those historically noted with conventional treatments. Disease subtypes such as prolymphocytic leukaemia and the prolymphocytoid variant of CLL are often resistant to first-line...