DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

After rapid extracellular dephosphorylation to the nucleoside
fludarabine, it is rephosphorylated intracellularly by deoxycytidine
kinase to the active triphosphate derivative. This antimetabolite
inhibits DNA polymerase, DNA primase, DNA ligase, and RNR and
becomes incorporated into DNA and RNA. The nucleotide is an
effective chain terminator when incorporated into DNA (Kamiya
et al., 1996), and the incorporation of fludarabine into RNA inhibits
RNA function, RNA processing, and mRNA translation (Plunkett
and Gandhi, 1993).
In experimental tumors, resistance to fludarabine is associated
with decreased activity of deoxycytidine kinase (the enzyme
that phosphorylates the drug) (Mansson et al., 2003), increased drug
efflux, and increased RNR activity. Its mechanism of immunosuppression
and paradoxical stimulation of auto-immunity stems from
the particular susceptibility of lymphoid cells to purine analogs and
the specific effects on the CD4 + subset of T cells, as well as its inhibition
of regulatory T-cell responses.
Absorption, Fate, and Excretion. Fludarabine phosphate is administered
both intravenously and orally and rapidly converts to fludarabine
in the plasma. The median time to reach maximal concentrations
of drug in plasma after oral administration is 1.5 hours, and oral
bioavailability averages 55-60%. The terminal t 1/2
of fludarabine in
plasma is ~10 hours. The compound is primarily (40-50%) eliminated
by renal excretion.
Therapeutic Uses. Fludarabine phosphate (FLUDARA, OFORTA) is
approved for intravenous and oral use and is equally active by both
routes (Forconi et al., 2008). The recommended dose of fludarabine
phosphate is 25 mg/m 2 daily for 5 days by intravenous infusion, or
40 mg/m 2 daily for 5 days by mouth. The drug is administered intravenously
over 30 minutes to 2 hours. Dosage should be reduced in
patients with renal impairment in proportion to the reduction in CrCl.
Treatment may be repeated every 4 weeks, and gradual improvement
in CLL usually occurs within two to three cycles.
Fludarabine phosphate is highly active alone or with rituximab
and cyclophosphamide for the treatment of patients with
CLL. Activity in CLL as a single agent is equal by either the oral
or intravenous routes, as overall response rates in previously
untreated patients approximate 80% and the duration of response
averages 22 months. The synergy of fludarabine with alkylators
may stem from the observation that it blocks the repair of doublestrand
DNA breaks and interstrand cross-links induced by alkylating
agents. It also is effective in follicular B-cell lymphomas
refractory to standard therapy. It is increasingly used as a potent
immunosuppressive agent in nonmyeloablative allogeneic bone
marrow transplantation, where it suppresses the host response and
may encourage alloreactive donor T cells.
Clinical Toxicities. Oral and intravenous therapy cause myelosuppression
(World Health Organization grade 3 or 4) in about half of patients,
nausea and vomiting in a minor fraction, and uncommonly chills and
fever, malaise, anorexia, peripheral neuropathy, and weakness.
Lymphopenia and thrombocytopenia and cumulative side effects are
expected. Depletion of CD4 + T cells with therapy predisposes to opportunistic
infections. Tumor lysis syndrome, a relatively infrequent complication,
occurs primarily in previously untreated patients with CLL.
Altered mental status, seizures, optic neuritis, and coma have been
observed at higher doses and in older patients.
Auto-immune events may occur after fludarabine treatment.
CLL patients may develop an acute hemolytic anemia or pure red
cell aplasia during or following fludarabine treatment. Prolonged
cytopenias, probably mediated by auto-immunity, also complicate
fludarabine treatment. Myelodysplasia and acute leukemias may
arise as late complications (Tam et al., 2008). Pneumonitis is an
occasional side effect and responds to corticosteroids. Because a significant
fraction of drug is eliminated in the urine, patients with compromised
renal function should be treated with caution, and initial
doses should be reduced in proportion to the reduction in CrCl.
Cladribine
An adenosine deaminase-resistant purine analog, cladribine
(2-chlorodeoxyadenosine; 2-CdA), has potent and
probably curative activity in hairy cell leukemia, CLL,
and low-grade lymphomas. It is taken up by active nucleoside
transport. After intracellular phosphorylation by
deoxycytidine kinase and conversion to cladribine
triphosphate, it is incorporated into DNA. It produces
DNA strand breaks and depletion of NAD and ATP, leading
to apoptosis. It is a potent inhibitor of RNR. The drug
does not require cell division to be cytotoxic. Resistance
is associated with loss of the activating enzyme, deoxycytidine
kinase; increased expression of RNR (Cardoen
et al., 2001); or increased active efflux by ABCG2 or
other members of the ABC cassette family of transporters
(de Wolf et al., 2008).
Cl
N
HOCH 2
NH 2
N
HO
Absorption, Fate, and Excretion. Cladribine is moderately
well absorbed orally (55%) but is routinely administered
intravenously. The drug is excreted by the
kidneys, with a terminal t 1/2
in plasma of 6.7 hours
(Liliemark and Juliusson, 1991). Cladribine crosses the
blood-brain barrier and reaches CSF concentrations of
~25% of those seen in plasma. Doses should be
adjusted for renal dysfunction.
Therapeutic Uses. Cladribine (LEUSTATIN, others) is
administered as a single course of 0.09 mg/kg/day for
7 days by continuous intravenous infusion.
O
CLADRIBINE
N
N
1703
CHAPTER 61
CYTOTOXIC AGENTS