Nursing Pharmacology Chapter 33-34:  Anticancer Drugs

• Antimetabolites

  • Antifolate Analogues: Methotrexate continued

    • Absorption, Distribution, Biotransformation, Excretion:¹  

      • Methotrexate is absorbed from the G.I. tract readily, although higher doses may be absorbed incompletely.

        • For higher doses, intravenous administration may be preferable.

          • At the higher doses, doses exceeding 25 mg/m² oral bioavailability becomes saturated and may be unreliable.³  

            • .At typical methotrexate doses, CSF levels may be only about 3% compared to that in the systemic circulation at steady-state.

              • However, at high dose methotrexate, cytotoxic methotrexate levels can be found in the CNS, the drug having crossed the blood-brain barrier.¹

        • Following IV administration, the drug moves from plasma to other compartments, in a triphasic manner.^1,11

          • The initial phase is one of rapid distribution with the second phase indicative of renal clearance showing a t1/2 of about 2-3 hours.

            • Renal excretion represents the primary route of elimination (glomerular filtration as well as tubular secretion). If the patient exhibits renal dysfunction, dosage modification may be appropriate.³

          • The last phase, the third phase, exhibits a half-life of about 9 hours.

            • This final phase, the terminal phase may be extended due to renal failure and may be causative of significant drug toxicity which references bone marrow, skin, and G.I. epithelium.

              • Methotrexate distribution into body compartments evolve slowly.

              • Plural or peritoneal sites, if larger than normal due to ascites or pleural effusion, may serve as a significant story site which promotes extended slow drug release with elevation of plasma levels and more prominent bone marrow toxicities.¹

              • Other drugs may inhibit methotrexate renal excretion and predisposed to methotrexate toxicities.

              These drugs include aspirin, nonsteroidal anti-inflammatory drugs, probenecid, cephalosporins as well as penicillin.^3,8

          • Methotrexate:  Pharmacokinetics

            Attribution:  Earle S Methotrexate: Kinetics https://www.youtube.com/watch?v=QE-PIJYsVZg (10/2012) Sandra Earle Youtube Channel:  https://www.youtube.com/channel/UCjyJXwXRe9U3GHdD3yrAfew/videos

        • About half of methotrexate is found bound to plasma proteins, primarily albumin, and may be displaced from these proteins by many drugs.

          • Examples of drugs that displace bound (inactive while bound) methotrexate from plasma proteins include chloramphenicol, phenytoin, tetracycline, salicylates and sulfonamides.

            • The expectable steady-state levels of methotrexate may be increased if these drugs are given along with methotrexate.

              • Given the dependence of methotrexate upon the kidneys for excretion (as much as 90%), drugs that decrease renal blood flow (the nonsteroidal anti-inflammatory drugs do this) can reduce methotrexate excretion which in turn can promote significant myelosupression.

              • Other mechanisms that reduce renal excretion of methotrexate include the presence of drugs that are inherently nephrotoxic or that are classified as weak organic acids

    • Pharmacogenomics¹:

      • Genetic changes can also influence cellular responses to antifolates as well as change baseline toxicities.¹

        • For example, a substitution (C677T) in methylenetetrahydrofolate reductase decreases enzyme activity involved in catalyzing N^5-10 methylene FH₄, the thymidylate synthase cofactor.

          • As a consequence, methotrexate toxicity is enhanced.

            • This particular pharmacogenetic effect, a leukemic cell polymorphism, would be associated with increased methotrexate sensitivity.

              • The 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene is localized at the end of the short arm of chromosome 1.12  This enzyme is important in folate metabolism since it irreversibly converts 5, 10-methylenetetrahydrofolate to 5-methylenetetrahydrofolate which is the major circulating folate form. Two common single nucleotide polymorphisms in MTHFR have been described.12 The first is a C → T transition at nucleotide number 677 at exon 4 and a second is an  A → C transversion in exon 7 at position 1298. Both of these changes are associated a functional enzyme with diminished enzymatic activity. The frequency of the C677T allele is associated with significant ethnic and geographic variation. For example, a high allele frequency is noted in California Hispanics whereas US Blacks exhibit a low allele frequency.12

        • Also, toxicity and therapeutic effects of another antifolate analog, pemetrexed (an important thymidylate synthase inhibitor) might also be influenced.¹

        • Another polymorphism, this time associated with the thymidylate synthase promoter region would alter the enzyme's expression.

          • The resultant change in intracellular thymidylate synthase concentrations would be expected to alter response as well as toxicity of both antifolates and fluoropyrimidines.¹

    • Toxicities and Adverse Effects:^8,1 

      • Some Methotrexate-Associated Toxicities

        Attribution:  Halee-rocha Incidence of Delays in Chemotherapy Due to Methotrexate Toxicity in Treatment of Osteosarcoma. https://www.slideserve.com/halee-rocha/incidence-of-delays-in-chemotherapy-due-to-methotrexate-toxicity-in-treatment-of-osteosarcoma Slide 7, 2014.

         

      • The primary methotrexate side effects our gastrointestinal (G.I.) toxicities and myelosupression.⁸ 

        • Patients receiving methotrexate may also experience spontaneous hemorrhage or serious, life-threatening infection.

          • In some circumstances platelet transfusions may be appropriate prophylactically as would be administration of broad-spectrum antibiotics.¹

        • The side effects are usually reversible within 2 weeks, assuming drug-elimination systems are intact.⁸ 

          • However, in patients with renal dysfunction, small methotrexate doses can lead to significant toxicities.⁸ 

            • These toxicities result from the substantial dependence on the kidneys for drug excretion.

              • Intratubular methotrexate precipitation and precipitation of its metabolites in acidic urine can lead to MTX-induced nephrotoxicity.

              • Additionally, antifolate drugs may be a direct toxicant for renal tubules.

            • For patients on high-dose methotrexate treatment there is a risk for hyperbilirubinemia in acute increases in hepatic enzyme levels.

              • Elevated levels typically are of limited duration, returning to normal within about 10 days.

          • For some treatment protocols, methotrexate is given along with radiation therapy.⁸ 

            • Such combinations appeared increase likelihood of soft tissue necrosis and osteonecrosis.

            • Initially high-dose methotrexate treatment incorporated an idea of selective normal tissue rescue through the use of reduce folate leukovorin.

            • High-dose methotrexate however may also be effective in mitigating resistance mechanisms due to:

              • Damaged active transport

              • Reduced dihydrofolate reductase (target) affinity for methotrexate

              • Increased dihydrofolate reductase concentrations due to gene amplification as well as by

              • Reduced polyglutamation of methotrexate.⁸

        • Methotrexate administration may also be associated with additional side effects/toxicities including: ¹

          • Alopecia

          • Allergic, interstitial pneumonitis

          • Dermatitis

          • Defective oogenesis or spermatogenesis

          • Teratogenesis.¹

        • Methotrexate Toxicities

          Attribution: Earle S Methotrexate Toxicities https://www.youtube.com/watch?v=xctEKY4AXj8 (10/2012) Sandra Earle Youtube Channel:  https://www.youtube.com/channel/UCjyJXwXRe9U3GHdD3yrAfew/videos

      • Clinical Uses:¹ 

        • Acute Lymphoblastic Leukemia in Children:¹

          •  

            "Leukemia in Children"

            Attribution: Alverson B Leukemin in Children https://www.youtube.com/watch?v=KOMGMZeqqgA (5/2019) Lecturio Medical Youtube Channel:  https://www.youtube.com/channel/UCbYmF43dpGHz8gi2ugiXr0Q

          •  

            "Targeting Cancer:  The Story of Leukemia"

            Attribution:  NEJM video Targeting Cancer:  The Story of Leukemia https://www.youtube.com/watch?v=bSuwwRi0GHI  (4/2012) NEJMvideo Youtube Channel:  https://www.youtube.com/channel/UCqO3GxVYutcugyknCWdAcUA

        • Methotrexate is an especially important drug for managing childhood occurrences of acute lymphoblastic leukemia (ALL).

        • Usefulness of high-dose methotrexate includes:

          • Induction of remission

          • Consolidation, and

          • Maintenance of remission.

        • In this setting, ALL is considered a highly curable malignancy.

          • Specific dosing protocols are associated with induction, including leukovorin rescue and maintenance treatment.

          • In children treatment outcome appears inversely associated with the rate of drug clearance.

          • During methotrexate infusion, relatively higher study-state concentrations appear correlated with a decreased likelihood of leukemia relapse rates.

        • By contrast, in acute myelogenous leukemia (AML), methotrexate has much more limited usefulness with the exception of treating and prevention of leukemic meningitis.

        • For treatment for prevention of meningeal leukemia or lymphoma and for treatment of meningeal carcinomatosis methotrexate may be employed by the intrathecal route of administration.

          • Using this approach, high concentrations of methotrexate in the CSF can be obtained and the treatment appears effective even in those patients exhibiting systemic disease which exhibits resistance to methotrexate.

        • Methotrexate is also useful in choriocarcinoma treatment and in this context the drug is administered by the intramuscular route in a manner that allows alternating administration with leukovorin.¹

        • Methotrexate may also be combined with other chemotherapeutic drugs.¹ 

          • For example, methotrexate is part of combination treatment for Burkett and other non-Hodgkin lymphomas.

          • Breast carcinoma, head and neck cancer, ovarian cancer and bladder cancer also benefit by protocols that include methotrexate.

          • High-dose methotrexate with leukovorin rescue (HDM-L) is considered standard for adjuvant treatment of osteosarcoma and is associated with a high response rate in CNS lymphoma.

            • Administration of high-dose methotrexate with leukovorin may cause renal toxicity due to drug precipitation in acidic tubular fluid.

            • This adverse effect may be mitigated by prophylactic vigorous hydration and urinary alkalinization.¹

        • Methotrexate:  Primary Therapeutic Applications⁸

          Non-Hodgkin's Lymphoma	Primary CNS Lymphoma	Acute Lymphoblastic Leukemia
          Breast Cancer, Bladder Cancer	Osteogenic Sarcoma	Gestational Trophoblastic Cancer