      Document 0064
 DOCN  DRG0064
 UNIQUE IDENTIFIER        DRG-0183
 NAME OF SUBSTANCE        Trimetrexate glucuronate [USAN 1996]
 REGISTRY NUMBER          82952-64-5
 STANDARD CHEMICAL NAME   2,4-Diamino-5-methyl-6-((3,4,5-trimethoxyanil-
                          ino) methyl)-quinazoline mono-D-glucuronate
                          [USAN 1996]
 SYNONYMS                 Trimetrexate D-glucuronate [Merck Index 1989]
 SYNONYMS                 NeuTrexin [Facts and Comparisons 1995]
 SYNONYMS                 Oncotrex [Merck Index 1989]
 PROTOCOL ID NUMBERS      NIAID ACTG 018
 PROTOCOL ID NUMBERS      NIAID ACTG 029
 PROTOCOL ID NUMBERS      NIAID ACTG 030
 PROTOCOL ID NUMBERS      NIAID ACTG 031
 PROTOCOL ID NUMBERS      NIAID ACTG 039
 PROTOCOL ID NUMBERS      FDA 132A
 PROTOCOL ID NUMBERS      FDA 132B
 PROTOCOL ID NUMBERS      FDA 132C
 PROTOCOL ID NUMBERS      FDA 132D
 PROTOCOL ID NUMBERS      NS 401
 PROTOCOL ID NUMBERS      TX 301
 PROTOCOL ID NUMBERS      FDA 224A
 PROTOCOL ID NUMBERS      NIAID 88 CC-85
 SECONDARY SOURCE ID      NSC-352122 [Merck Index 1989]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Trimetrexate is a potent
                          inhibitor of dihydrofolate reductase. It is
                          more lipophilic than methotrexate and this is
                          assumed to account for its better penetration
                          into P. carinii. The drug can produce
                          considerable myelosuppression due to its
                          antifolate action; however, administration
                          with leucovorin allows differential rescue of
                          host tissues without reversal of the
                          anti-protozoal effect. Trimetrexate has a
                          mean oral bioavailability of 44% (range, 19%
                          to 67%); therefore, it is administered
                          intravenously. The drug is extensively
                          protein bound (95%). Unlike methotrexate,
                          which is excreted mainly unchanged in the
                          urine, trimetrexate is extensively
                          metabolized by the liver. At least two
                          metabolites are active and two are conjugated
                          with glucuronic acid. The hepatic degradation
                          may account for the low and variable oral
                          absorption. The terminal elimination
                          half-life is 15-20 hours. [Drug Evaluations
                          Annual 1992] [Facts and Comparisons 1995]
                          [PDR 1995]
 DISEASES STUDIED/TREATED FDA approved 12/20/93 for use with concurrent
                          leucovorin administration as an alternative
                          therapy for the treatment of moderate to
                          severe Pneumocystis carinii pneumonia (PCP)
                          in immunocompromised patients [FDA Press
                          Release] [PDR 1995]
 DISEASES STUDIED/TREATED This includes those with AIDS, who are
                          intolerant of, or are refractory to,
                          trimethoprim/sulfamethoxazole (TMP-SMX), or
                          for whom TMP-SMX is contraindicated [FDA
                          Press Release] [PDR 1995] [FDA Press Release]
 CLASSIFICATION CODE      Antifolate [US Bioscience drug insert
                          pamphlet on NeuTrexin]
 CLASSIFICATION CODE      Antiprotozoal [Drug Evaluations Annual 1992]
 CLASSIFICATION CODE      Antineoplastic [USAN 1996]
 ADVERSE EFFECTS          Fluctuating leukopenia and thrombocytopenia
                          and transient increases in serum
                          concentrations of aspartate and alanine
                          aminotransferases are observed commonly. No
                          infections have resulted from the leukopenia.
                          Leukopenia and thrombocytopenia respond
                          promptly to lowering the dose by 50%. Initial
                          three- to five- fold increases in serum
                          concentrations of aminotransferases gradually
                          are reversed when therapy is continued.
                          Mucositis (stomatitis), anemia, and skin
                          rashes occur occasionally; diarrhea,
                          arthraglia, fever, bleeding, anorexia,
                          nausea, and vomiting are reported even less
                          frequently. [Drug Evaluations Annual 1992]
                          [PDR 1995]
 CONTRAINDICATIONS        Contraindicated in patients sensitive to
                          trimetrexate, leucovorin, or methotrexate.
                          [PDR 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: A 2,4-diaminoquinazoline
                          [PDR 1995]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: Trimetrexate
                          glucuronate for injection is a pale
                          greenish-yellow powder or cake [PDR 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C19H23N5O3.C6H10O7 [USAN
                          1996]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 563.57 [USAN 1996]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Solubility in water: greater than
                          50 mg/ml [PDR 1995]
 CHEMICAL/PHYSICAL DATA   STABILITY: Precipitates if reconstituted with
                          solutions containing chloride ions or
                          leucovorin [PDR 1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Supplied as a sterile
                          lyophilized powder in 5 ml, single dose
                          vials. [PDR 1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Each 5 ml bottle contains
                          trimetrexate glucuronate equivalent to 25 mg
                          of trimetrexate. [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Reconstituted solutions are stable
                          for 24 h at room temperature or under
                          refrigeration. [PDR 1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Administered at a dose of
                          45 mg/m2 once daily by intravenous infusion
                          over 60-90 minutes. [PDR 1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Leucovorin must be
                          administered daily during treatment with
                          NeuTrexin and for 72 hours past the last
                          dose. [PDR 1995]
 MANUFACTURERS            US Bioscience, Incorporated
 REFERENCES               Drugs for AIDS and associated infections. Med
                          Lett Drugs Ther. 1995 Oct 13;37(959):87-94.
 REFERENCES               Chan JH, Hong JS, Kuyper LF, Baccanari DP,
                          Joyner SS, Tansik RL, Boytos CM, Rudolph SK.
                          Selective inhibitors of Candida albicans
                          dihydrofolate reductase: activity and
                          selectivity of
                          5-(arylthio)-2,4-diaminoquinazolines. J Med
                          Chem. 1995 Sep 1;38(18):3608-16.
 REFERENCES               Fulton B, Wagstaff AJ, McTavish D.
                          Trimetrexate. A review of its pharmacodynamic
                          and pharmacokinetic properties and
                          therapeutic potential in the treatment of
                          Pneumocystis carinii pneumonia. Drugs. 1995
                          Apr;49(4):563-76.
 REFERENCES               Freij BJ, Wientzen RL Jr., Hayek G, Whitfield
                          LR. Pharmacokinetics of trimetrexate
                          glucuronate in infants with AIDS and
                          Pneumocystis carinii pneumonia. Ann NY Acad
                          Sci. 1993 Oct 29;693:302-5.
 REFERENCES               Sattler FR, Frame P, Davis R, Nichols L,
                          Shelton B, Akil B, Baughman R, Hughlett C,
                          Weiss W, Boylen CT, et al. Trimetrexate with
                          leucovorin versus
                          trimethoprim-sulfamethoxazole for moderate to
                          severe episodes of Pneumocystis carinii
                          pneumonia in patients with AIDS: a
                          prospective, controlled multicenter
                          investigation of the AIDS Clinical Trials
                          Group Protocol 029/031. J Infect Dis. 1994
                          Jul;170(1):165-72.
 REFERENCES               Masur H, Polis MA, Tuazon CU, Ogata-Arakaki
                          D, Kovacs JA, Katz D, Hilt D, Simmons T,
                          Feuerstein I, Lundgren B, et al. Salvage
                          trial of trimetrexate-leucovorin for the
                          treatment of cerebral toxoplasmosis in
                          patients with AIDS. J Infect Dis. 1993
                          Jun;167(6):1422-6.
 REFERENCES               Vohringer HF, Arasteh K. Pharmacokinetic
                          optimisation in the treatment of Pneumocystis
                          carinii pneumonia. Clin Pharmacokinet. 1993
                          May;24(5):388-412.
 REFERENCES               Feinberg J, McDermott C, Nutter J.
                          Trimetrexate (TMTX) salvage therapy for PCP
                          in AIDS patients with limited therapeutic
                          options. Int Conf AIDS. 1992 Jul
                          19-24;8(2):B136 (abstract no. PoB 3297).
 REFERENCES               Amsden GW, Kowalsky SF, Morse GD.
                          Trimetrexate for Pneumocystis carinii
                          pneumonia in patients with AIDS. Ann
                          Pharmacother. 1992 Feb;26(2):218-26.
 REFERENCES               Sattler FR, Feinberg J. New developments in
                          the treatment of Pneumocystis carinii
                          pneumonia. Chest. 1992 Feb;101(2):451-7.
 ENTRY MONTH              9307
 LAST REVISION DATE       960417
 

SOURCE: National Library of Medicine, Bethesda, MD.  Distributed by AEGIS.
