Page 1014 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 897

anemia. Nausea and vomiting are mild. Other potential side effects Nelarabine, Arabinofuranosylguanine (Ara-G)
include diarrhea, fever, and hepatotoxicity, including hyperbilirubi-
nemia, transamination elevations, and electrolyte abnormalities. Chemistry and Mechanism of Action: Nelarabine is a prodrug
of the deoxyguanosine analog 9′-β-D-arabinofuranosylguanine, also
Drug Interactions: None reported. known as ara-G. Accumulation of a metabolite ara-GTP in leukemic
blasts allows for incorporation into DNA, leading to inhibition of
Therapeutic Indications in Hematology: Decitabine is indi- DNA synthesis and cell death.
cated for treatment of patients with MDS, including previously
treated and untreated, de novo, and secondary MDS. It has also been Absorption, Fate, and Excretion: Nelarabine is demethylated
used as salvage therapy both alone and in combination for AML, by ADA to ara-G, then monophosphorylated by deoxyguanosine
chronic myeloid leukemia, and acute lymphoid leukemia. kinase and deoxycytidine kinase, and subsequently converted to the
active 5′-triphosphate, ara-GTP. Nelarabine is only available in an IV
Gemcitabine formulation. Nelarabine and ara-G are both partially eliminated by
the kidneys. Approximately 5%–10% of nelarabine is excreted by the
Chemistry and Mechanism of Action: Gemcitabine kidneys compared with 20%–30% of ara-G. Nelarabine exhibits a
(2′,2′-difluorocytidine monohydrochloride) is a nucleoside analog half-life of 30 minutes, and ara-G, the active metabolite, has a half-
that differs from 2′-deoxycytidine by virtue of the presence of fluorine life of 3 hours.
atoms in the 2′α and 2′β positions of the cytidine ring. It is trans-
ported across the cell membrane by facilitated nucleoside diffusion, Preparation and Administration: Nelarabine for injection is
phosphorylated by deoxycytidine kinase, and ultimately converted to supplied as a clear, colorless, sterile solution in glass vials. Each vial
its lethal metabolites, dFdCDP and dFdCTP. The diphosphate form contains 250 mg of nelarabine (5 mg of nelarabine/mL) and sodium
(dFdCDP) inhibits ribonucleotide reductase, leading to disruption chloride (4.5 mg/mL) in 50 mL of water for injection, USP. Nelara-
of dNTP pools and resultant interference with DNA synthesis and bine is not diluted before administration. The dose is transferred into
repair. The triphosphate form (dFdCTP) competes with dCTP for polyvinylchloride (PVC) infusion bags or glass containers and admin-
incorporation into DNA. Reductions in dCTP pools (secondary to istered as a 2-hour infusion in adult patients or as a 1-hour infusion
ribonucleotide reductase inhibition) result in self-potentiation of in pediatric patients.
gemcitabine action. Incorporation of gemcitabine into DNA in S
phase inhibits elongation of the replicating strand, leading to DNA Toxic Effects: Bone marrow suppression encompassing all cell
chain termination. The lethal actions of gemcitabine in leukemia cells lines causing anemia, leucopenia, thrombocytopenia, and neutrope-
have been related to the induction of apoptosis and are not restricted nia occurs in all patients. Neurologic complications of nelarabine
to cells actively engaged in DNA synthesis. Gemcitabine has been include asthenia, altered mental states including severe somnolence,
shown to be considerably more potent in inducing apoptosis in CNS effects including convulsions, and peripheral neuropathy
cultured human leukemia cells than ara-C. ranging from numbness and paresthesias to motor weakness and
paralysis. Demyelinating disease of the CNS may occur when com-
Absorption, Fate, and Excretion: In studies involving IV bining nelarabine with other drugs that may have CNS toxicity.
administered labeled gemcitabine, up to 98% of the drug was recov- Nausea and vomiting are seen and antiemetics are necessary.
ered in the urine after 1 week. The excreted dose was composed
of a minor fraction (gemcitabine; <10%) and inactive metabolites Drug Interactions: Pentostatin has been shown to be a strong
(e.g., 2′-deoxy-2′,2′-difluorouridine). Plasma protein binding was inhibitor of ADA in vitro. Concurrent administration of nelarabine
minimal. In studies involving both short and long gemcitabine and pentostatin may result in reduced ADA-dependent conversion
infusions, the pharmacokinetics were found to be linear and best of nelarabine to its active moiety, thereby potentially decreasing
described by a two-compartment model. Plasma half-life and clear- nelarabine efficacy or altering nelarabine’s adverse event profile.
ance are influenced both by age and gender. For short infusions, Therefore, concomitant administration of nelarabine and pentostatin
half-lives varied from 32 to 94 minutes; for longer infusions, half-lives is not recommended.
varied from 245 to 638 minutes. The volume of distribution was
2
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approximately 50 L/m for short infusions and 370 L/m for long Therapeutic Indications in Hematology: Nelarabine is effec-
infusions. tive in T-cell ALL, T-cell lymphoma, and T-cell lymphoblastic lym-
2
phoma. The dosage in adults of nelarabine is 1500 mg/m
Preparation and Administration: Vials of gemcitabine contain administered IV over 2 hours on days 1, 3, and 5 repeated every 21
2
200 mg or 1 g of the HCl derivative formulated with mannitol days. The pediatric dosage of nelarabine is 650 mg/m administered
(200 mg or 1 g) and sodium acetate (12.5 mg or 62.5 mg) as a sterile IV over 1 hour daily for 5 consecutive days repeated every 21 days.
lyophilized powder. HCl or NaOH has been used for pH The proper number of cycles for adult and pediatric patients has not
adjustment. been determined.
Toxic Effects: The major dose-limiting toxicity of gemcitabine is Clofarabine
myelosuppression, although anemia and thrombocytopenia have also
been encountered. Other toxicities include nausea and vomiting, Chemistry and Mechanism of Action: Clofarabine is a purine
transient elevations in liver function test results, mild hematuria, nucleoside antimetabolite formulated in unbuffered normal saline
proteinuria (and in rare cases, hemolytic uremic syndrome), fever, with a pH range of 4.5–7.5. It inhibits DNA synthesis by decreasing
rash, dyspnea, edema, and a flulike syndrome. Other infrequent cellular deoxynucleotide triphosphate pools by inhibiting ribonucleo-
toxicities included alopecia, paresthesias, and bronchospasm. tide reductase, terminating DNA chain elongation, and inhibiting
repair through incorporation into the DNA chain by competitive
Potential Interactions: Gemcitabine may function as a radiosen- inhibition of DNA polymerases.
sitizing agent and can increase the toxicity of ionizing radiation. No
other interactions are known. Absorption, Fate, and Excretion: Clofarabine is 47% bound to
plasma proteins, primarily albumin. Clofarabine is phosphorylated
Indications in Hematology: The primary indication for gem- intracellularly to the cytotoxic active form (clofarabine triphosphate)
citabine is in the treatment of patients with pancreatic carcinoma. by deoxycytidine kinase. The terminal half-life is estimated to be 5.2
However, as an experimental agent, gemcitabine is being evaluated hours with the metabolite clofarabine triphosphate, yielding a half-
for the treatment of ALL and CLL. life greater than 24 hours, and 49%–60% of the dose is excreted in