Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, ATC code: L01B B05

Mechanism of action
Fludarabine phosphate contains fludarabine phosphate (2F-Ara-AMP), a water-soluble fluorinated nucleotide analogue of the antiviral agent vidarabine (Ara-A, 9-ß-D-arabinofuranosyladenine) 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 intracellularly phosphorylated by deoxycytidine kinase to active triphosphate, 2F-ara-ATP. This metabolite inhibits ribonucleotide reductase, DNA polymerase /β and , DNA primase and DNA ligase thereby preventing 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 believed that effects on DNA, RNA and proteinsynthesis all contribute to the 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 apoptosis with extensive DNA fragmentation.

Clinical efficacy and safety
In a phase-III-study including patients with previously untreated B-cell-CLL, 195 patients were treated with fludarabine and 199 patients with chlorambucil (40 mg/m2, repeated every 4 weeks).

The overall remission rate and the rate of complete remissions was statistically significant higher after first line treatment with fludarabine in comparison to chlorambucil 61% versus 37.6% and 19% versus 3.4%, respectively. The duration of remission (19 months versus 12.2 months) and time to progression (17 versus 13.2 months) were statistically significant longer with fludarabine treatment than with chlorambucil. Median survival was 56.1 months with fludarabine phosphate and 55.1 months with chlorambucil, a non-significant difference was also shown with performance status. The incidence of toxicities was comparable (89.7% with fludarabine phosphate, 89.9% with chlorambucil). Overall hematological toxicities were equally frequent, but a decrease of the counts of leucocytes and of lymphocytes was significantly more frequent with fludarabine phosphate than with chloramucil (p = 0.0054 and 0.0240, respectively). Nausea, vomiting and diarhoea was significantly less frequent with fludarabine phosphate than with chlorambucil (p < 0.0001, p < 0.0001, p = 0.0489, respectively).

Also, liver toxicities were reported for significantly (p = 0.0487) less patients in the fludarabine phosphate arm than in the chlorambucil arm.

Patients who initially respond to fludarabine phosphate have a good chance of responding again to fludarabine phosphate monotherapy.

A randomized study comparing fludarabine phosphate with a combination of cyclophosphamide plus adriamycin and prednisolon (CAP) in 208 patients with CLL (Binet stage B and C) showed in a subgroup of 103 pretreated patients the following results: The overall response rate and the number of complete remissions were higher with fludarabine phosphate compared to CAP (45% vs. 26% and 13% vs. 6%, respectively); response duration and overall survival were similar with fludarabine phosphate and CAP. Within the stipulated treatment period of 6 months the number of deaths was 9 (fludarabine phosphate) vs. 4 (CAP).
Post-hoc analyses using data of up to 6 months after start of treatment revealed a difference between survival curves of fludarabine phosphate and CAP in favour of CAP in the subgroup of pre-treated Binet stage C patients.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Plasma and urine pharmacokinetics of fludarabine (2F-ara-A)
The pharmacokinetic properties of fludarabine phosphate were investigated after intravenous bolus injection and after short and long term intravenous infusion of fludarabine phosphate (2F-ara-AMP) in patients with malignant diseases.

Distribution and Biotransformation
2F-ara-AMP is a water-soluble prodrug, which is rapidly and quantitatively dephosphorylated in the human organism to the nucleoside fludarabine (2F-ara-A). After cancer patients had received a single infusion of 25 mg 2F-ara-AMP per m² to over 30 minutes, 2F-ara-A reached mean maximum concentrations in the plasma of 3.5-3.7μM at the end of the infusion. Corresponding 2F-ara-A levels after the fifth dose showed a moderate accumulation with mean maximum levels of 4.4-4.8µM at the end of the infusion. During a 5-day treatment period, 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 ruled out. Post maximum levels of 2F-ara-A were reduced in three disposition phases with an initial half-life of approx. 5 minutes, an intermediate half-life of 1-2 hours and a terminal half-life of approx. 20 hours.

An inter-study comparison of 2F-ara-A pharmacokinetics resulted in a mean overall 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 inter-individual variability. Plasma levels of 2F-ara-A and areas under the plasma level time curves increased linearly with the dosage, whereas half-lives, plasma clearance and volumes of distribution remained constantly dose independent, indicating a dose linear behaviour.

Occurrence of neutropenia and haematocrit changes indicated that cytotoxicity of fludarabine phosphate causes dose dependent haematopoiesis inhibition.

Elimination
The main pathway of 2F-ara-A elimination leads via the kidneys. 40 to 60% of the administered IV dose was excreted in the urine. Mass balance studies in laboratory animals with ³H-2F-ara-AMP showed that the radio-tagged substances were completely excreted in the urine. 2F-ara-hypoxanthine, which is the major metabolite in dogs, was observed in humans only in small amounts. Since patients with impaired renal function have a reduced total body clearance of 2F-ara-A, dose reduction is required in these cases. In vitro studies with human plasma proteins showed no pronounced tendency of 2F-ara-A protein binding.

Cellular pharmacokinetics of fludarabine triphosphate

2F-ara-A is actively absorbed into leukemic cells, whereupon it is rephosphorylated to mono- and diphosphate and subsequently to triphosphate. Fludarabine triphosphate, 2F-ara-ATP, is the major intracellular metabolite and the only one known to have cytotoxic activity. Maximum 2F-ara-ATP levels in leukemic lymphocytes of CLL patients were observed approx. 4 hours after application and exhibited a considerable variation around a median peak concentration of approx. 20µM. 2F-ara-ATP levels in leukemic cells were considerably higher than maximum 2F-ara-A plasma levels indicating an accumulation in the target cells. In vitro incubation of leukemic lymphocytes showed a linear relationship between extracellular 2F-ara-A exposure (product of 2F-ara-A concentration and incubation time) and intracellular 2F-ara-ATP enrichment. 2F-ara-ATP elimination from target cells showed median half-life values of 15 and 23 hours.

No clear correlation was found between 2F-ara-A pharmacokinetics and treatment efficacy in cancer patients.