Page 1009 - Hematology_ Basic Principles and Practice ( PDFDrive )

892 Part VII Hematologic Malignancies

A P P E N D I X 57.3

CLINICAL PHARMACOLOGY OF ANTIMETABOLITES

Cytosine Arabinoside ones. These include alopecia, an exfoliative dermatitis, a chemical
conjunctivitis (generally ameliorated by the prophylactic administra-
Chemistry and Mechanism of Action: Cytosine arabinoside tion of a steroid or saline ophthalmic solution), a respiratory distress–
(1′-β-D-arabinofuranosylcytosine; ara-C) is a nucleoside analog that like syndrome (characterized by the appearance of rales, abnormal
differs from its naturally occurring counterpart (2′-deoxycytidine) by radiography findings, and pulmonary insufficiency), and cerebellar
virtue of the presence of a hydroxyl group in the 2′-β configuration. toxicity. The latter, which is characterized by nystagmus, ataxia, and
The altered reactivity of the resulting arabinosyl sugar moiety confers other cerebellar signs, may be irreversible, and its appearance man-
on ara-C its cytotoxic activity. Ara-C enters the cell by a facilitated dates discontinuation of therapy. Intrathecal administration of ara-C
nucleoside diffusion mechanism and is converted to its nucleoside has been rarely associated with the toxicities described later for
monophosphate form, ara-CMP, by the pyrimidine salvage pathway methotrexate.
enzyme, deoxycytidine kinase. This represents the rate-limiting step
in ara-C metabolism. Ara-C may also be catabolized intracellularly Potential Drug Interactions: None reported.
to an inactive form, ara-U, by the enzyme cytidine deaminase (CDD).
Ara-C is ultimately converted to its lethal triphosphate derivative, Therapeutic Indications in Hematology: Ara-C represents a
ara-CTP, by a mono- and diphosphate kinase. Ara-CTP is an inhibi- mainstay in the treatment of AML (e.g., as part of the “7 and 3”
tor of DNA polymerases α, β, and γ, and is also incorporated into regimen, in which it is given in conjunction with daunorubicin). It
replicating DNA strands, leading to inhibition of chain initiation and is also incorporated into some induction regimens for ALL. High-
elongation and premature chain termination. The extent of incorpo- dose ara-C (HIDAC), either alone or in combination with anthracy-
ration of ara-C into DNA closely correlates with lethality in leukemic cline antibiotics, is frequently used in the treatment of refractory or
cells. Although ara-C is generally thought of as a prototypical relapsed AML or ALL. High-dose ara-C has also been used in some
S-phase–specific agent, its ability to interfere with DNA repair salvage regimens for NHL (e.g., ESHAP). Chronic low-dose ara-C
polymerases (e.g., β and γ) as well as lipid biosynthetic enzymes may has been used in the treatment of patients with myelodysplastic
account for lethal effects in noncycling cells. syndrome (MDS).
Absorption, Fate, and Excretion: After IV administration, Methotrexate
ara-C is rapidly deaminated to an inactive form, ara-U, by CDD.
This enzyme is present in the plasma, liver, and kidney but is present Chemistry and Mechanism of Action: Methotrexate (N-[4-
at very low levels in the CNS. The initial plasma half-life of ara-C [[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-
has been estimated to be 10–12 minutes. Approximately 90% of the glutamic acid) represents a member of a class of compounds referred
administered ara-C dose is excreted by the kidneys as ara-U or other to as antifolates. Methotrexate is a potent inhibitor of dihydrofolate
inactive metabolites. The terminal half-life of ara-C is approximately reductase, an enzyme responsible for the reduction of dihydrofolates
2–3 hours. CNS ara-C levels after a 2-hour infusion approximate to tetrahydrofolates. The latter are required in 1-carbon transfer
50% of plasma concentrations. Steady-state plasma concentrations reactions involved in de novo purine and pyrimidine biosynthesis,
2
after standard-dose therapy (e.g., 100–200 mg/m /day as a continu- including conversion of deoxyuridylate (dUMP) to thymidylate
−7
−6
ous infusion) approximate between 10 and 10 M. When ara-C is (dTMP) by thymidylate synthase. As in the case of most antimetabo-
2
given as a high-dose bolus infusion (e.g., 1–3 g/m over 1–3 hours), lites, methotrexate is primarily active against S-phase cells. Metho-
plasma levels as high as 100 µM can be achieved. trexate is transported across cell membranes by an energy-dependent,
temperature-sensitive concentrative process involving folate-binding
Preparation and Administration: Ara-C is provided as a sterile, proteins, after which it is polyglutamylated by the enzyme folylpoly-
lyophilized powder for reconstitution in vials containing 100 mg, glutamyl synthetase. Polyglutamylation of methotrexate enhances its
200 mg, 1 g, or 2 g of material. The powder is reconstituted with intracellular retention and in some studies has been shown to cor-
sterile bacteriostatic water for injection with benzyl alcohol (0.945%) relate with the sensitivity of leukemic cells to this agent. The mecha-
added as a preservative. When reconstituted in this way, solutions are nism by which methotrexate kills cells may stem from interference
stable for up to 48 hours under controlled temperatures (e.g., between with DNA synthesis (leading to a “thymine-less death”) secondary to
15°C and 30°C or 60°F and 86°F). Material reconstituted without DHFR inhibition, disruption of purine biosynthesis, or a combina-
preservative should be used immediately. For intrathecal injection, tion of these actions. The lethal actions of methotrexate may be
ara-C should be reconstituted in a diluent that does not contain reversed by reduced folates such as 5-formyltetrahydrofolate (leucovo-
preservative (e.g., preservative-free 0.9% sodium chloride, USP) and rin). The possibility that tumor cells may exhibit impaired transport
used immediately. of such reduced folates serves as the basis for strategies involving
administration of high-dose methotrexate in conjunction with leu-
Toxic Effects: Ara-C is primarily toxic to rapidly dividing tissues; covorin rescue.
consequently, myelosuppression and gastrointestinal toxicity repre-
sent the major side effects of this agent. Patients receiving ara-C regu- Absorption, Fate, and Excretion: In adults, oral absorption
larly experience leukopenia, anemia, and thrombocytopenia, with is dose dependent, with mean bioavailability approximating 60%
2
2
nadirs appearing 7–14 days after drug administration. Gastrointestinal at doses of 30 mg/m or less. At higher doses (e.g., ≥80 mg/m ),
toxicity includes nausea and vomiting, abdominal pain, mucositis, bioavailability is less. Peak plasma concentrations occur 1–2 hours
and a chemical hepatitis characterized by elevation of liver function after oral administration. Methotrexate bioavailability approximates
enzymes. The latter is generally reversible. Patients receiving ara-C as 100% for parenteral routes of administration; with these routes,
2
a high-dose infusion (e.g., 1–3 g/m repeated every 12 hours for a peak plasma methotrexate levels are achieved within 30–60 minutes
total of 6–12 doses) experience standard toxicities and several unique after administration. For each route, the steady-state volume of