Page 1010 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 893

distribution ranges from 40% to 80% of body weight. Methotrexate A necrotizing leukoencephalopathy has been reported in patients
tends to accumulate in third-space fluids (e.g., ascites or pleural receiving methotrexate who have had prior cranial irradiation. Intra-
effusions) and can result in prolonged release and accompanying thecal methotrexate has been associated with several toxicities,
toxicity. Consequently, it is generally not advisable for patients with including (1) chemical arachnoiditis; (2) motor paralysis accompa-
fluid accumulations to receive methotrexate. Methotrexate competes nied by cranial nerve dysfunction, seizures, and coma; and (3) chronic
with reduced folates for transport across cell membranes; however, demyelinating syndrome. Each of these may be exacerbated by prior
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at high doses (e.g., ≥100 mg/m ), passive diffusion is the primary craniospinal irradiation.
mechanism through which intracellular accumulation occurs.
Methotrexate is approximately 50% protein bound and does not Potential Drug Interactions: Methotrexate exhibits many poten-
penetrate the CNS barrier when administered orally or parenter- tial drug interactions that are related to plasma protein binding. For
ally at conventional doses. However, when given by the intrathecal example, many compounds are known to displace methotrexate from
route, high CNS levels are achieved. Administration of high-dose serum albumin, potentially increasing its bioavailability. These agents
methotrexate with leucovorin rescue can also result in therapeutic include sulfonamides, salicylates, tetracyclines, chloramphenicol, and
CNS levels. phenytoin. However, the clinical implications of such interactions
The primary route of excretion is renal, with 80%–90% of the are not clear. Nonsteroidal antiinflammatory drugs should not be
drug appearing unchanged in the urine within 24 hours after IV administered in conjunction with methotrexate when the latter
administration. The terminal half-life of methotrexate is 4–10 hours is given at intermediate or high doses owing to the potential for
for patients receiving low-dose therapy and 8–15 hours for those elevation and prolongation of methotrexate plasma concentrations.
receiving high-dose therapy. Because of the primary renal rate of Penicillins can reduce renal clearance of methotrexate and should
excretion and the possibility of nephrotoxicity, methotrexate should be used with caution in this setting. Probenecid may also reduce
be withheld or administered at reduced doses in patients with renal transport of methotrexate. Administration of methotrexate can
impaired renal function. Patients receiving high-dose methotrexate also reduce the clearance of theophyllines, and concomitant use of
therapy should be hydrated and their urine alkalinized before admin- these agents requires careful monitoring. Increases in methotrexate
istration to reduce the risks of toxicity. toxicity have been observed in some patients receiving trimethoprim–
sulfamethoxazole, possibly as a consequence of enhanced antifolate
Preparation and Administration: Methotrexate is available in effects. Administration of folates in vitamin preparations may reduce
multiple formulations: (1) tablets, containing 2.5 mg methotrexate the efficacy of methotrexate by bypassing dihydrofolate reductase
and inactive ingredients (lactose, magnesium stearate, and pregelati- inhibition. Methotrexate may increase the toxicity (and potentially
nized starch; (2) methotrexate sodium injection, available in vials of the activity) of various antineoplastic agents in a schedule-dependent
25, 50, and 250 mg, containing benzyl alcohol as a preservative, manner (e.g., when given before 5-fluorouracil).
sodium chloride, and water for injection (preservative-containing
solutions should not be used for intrathecal or high-dose administra- Therapeutic Indications in Hematology: Methotrexate is
tion); (3) methotrexate sodium injection without preservative, which widely used in the treatment of ALL, particularly in the maintenance
can be used for IV, intraarteriolar, intrathecal, and high-dose admin- phase. Methotrexate is frequently administered intrathecally in
istration; and (4) lyophilized powder, which is provided in 20-mg patients with CNS leukemia and prophylactically in certain patients
vials and is reconstituted with preservative-free sodium chloride or with ALL. It also represents a component of various multidrug regi-
5% dextrose in water to a final concentration not exceeding mens used in the treatment of NHL (e.g., M-BACOD,
25 mg/mL. PROMACE-CYTABOM).
For intrathecal administration, solutions of 1–1.5 mg/mL should
be prepared using preservative-free 0.9% sodium chloride as the Hydroxyurea
diluent. For high-dose therapy, leucovorin rescue is required to
prevent significant toxicity. Leucovorin is administered 12–24 hours Chemistry and Mechanism of Action: Hydroxyurea is an
after methotrexate at a dose of between 15 and 25 mg IV, intramus- inhibitor of the ribonucleotide reductase system that catalyzes
cularly (IM), or PO every 6 hours until the methotrexate dose the rate-limiting step in the de novo biosynthesis of purine and
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declines to levels of less than 5 × 10 M. pyrimidine deoxyribonucleotides, that is, the conversion of ribo-
For patients receiving intermediate or high-dose methotrexate nucleotide diphosphates to their deoxyribonucleoside diphosphate
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(e.g., ≥500 mg/m ), serum methotrexate and creatinine levels should derivatives. Ribonucleotide reductase consists of two subunits:
be monitored at 24-hour intervals. If, after 48 hours serum metho- a binding and allosteric effector component and an iron-binding
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trexate levels are greater than 5 × 10 M but less than 1 × 10 M, catalytic component. Hydroxyurea binds to and inactivates the
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leucovorin is continued at a dose of 25 mg/m every 6 hours for eight catalytic subunit of the enzyme. Similar to most antimetabolites,
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doses until methotrexate levels decline to below 5 × 10 M. If levels hydroxyurea is an S-phase–specific agent and blocks cells in the
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are greater than 1 × 10 M but less than 2 × 10 M at 48 hours, G 1 S phase of the cell cycle. Exposure of cells to hydroxyurea leads
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the dose of leucovorin is increased to 100 mg/m every 6 hours for to a depletion of deoxyribonucleotide triphosphate (dNTP) pools,
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eight doses. For methotrexate levels ≥2 × 10 M at 48 hours, the the extent of which correlates with DNA synthesis inhibition
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dose of leucovorin is 200 mg/m every 6 hours for eight doses. and cell death. Two consequences of hydroxyurea administration
include potentiation of the metabolism or cytotoxicity of nucleo-
Toxic Effects: Methotrexate primarily exhibits its toxic effects side analogs (e.g., ara-C) as a result of dNTP pool depletion and
toward proliferating tissues. Consequently, dose-limiting toxicities elimination of amplified genes present extrasomally in double-minute
include bone marrow suppression (leukopenia, thrombocytopenia, chromosomes.
anemia), mucositis, and diarrhea. High-dose therapy is occasionally
accompanied by transient elevations in liver function test results, but Absorption, Fate, and Excretion: Hydroxyurea is generally
chronic low-dose therapy is more often associated with hepatic administered PO, although IV regimens are currently being investi-
fibrosis. Standard-dose therapy is rarely associated with nephrotoxic- gated. The drug is readily absorbed from the gastrointestinal tract,
ity, but acute renal failure can be seen with high-dose therapy second- with peak plasma levels as high as 2.0 mM occurring approximately
ary deposition of 7-OH-methotrexate in the renal tubules. The risk 2 hours after oral administration. Serum concentrations decline to
of methotrexate nephrotoxicity is significantly reduced by ensuring undetectable levels after 24 hours. The drug is primarily excreted via
adequate hydration and alkalinization of the urine. Other reported the renal route, with 75%–80% of the drug appearing in the urine
toxicities include a maculopapular rash and an idiosyncratic pulmo- 12 hours later. The drug penetrates the cerebrospinal fluid, although
nary toxicity characterized by cough, fever, dyspnea, hypoxia, and it has not been established that therapeutic levels are achieved after
interstitial infiltrates. standard oral administration.