      Document 0150
 DOCN  DRG0150
 UNIQUE IDENTIFIER        DRG-0097
 NAME OF SUBSTANCE        3'-Deoxy-3'-Fluorothymidine [Int Conf AIDS
                          1992 Jul 19-24;8(2):B91 (abstract no PoB
                          3025)]
 REGISTRY NUMBER          25526-93-6
 STANDARD CHEMICAL NAME   3'-Deoxy-3'-Fluorothymidine [CHEMLINE]
 SYNONYMS                 FLT [AmFAR Tx Dir 1993;6(3)]
 SYNONYMS                 3'-Fluoro-3'-Deoxythymidine [Antimicro Agents
                          Chemother 1990 June]
 SYNONYMS                 3'-Fluorothymidine [AmFAR Tx Dir April, 1991]
 SYNONYMS                 FDT [Antimicro Agents Chemother 1990 June]
 SYNONYMS                 FddT [Antimicro Agents Chemother 1990 June]
 SYNONYMS                 FT [Antimicro Agents Chemother 1990 June]
 SYNONYMS                 3'-fluoro-2',3'-dideoxythymidine [MeSH]
 SYNONYMS                 1-(3'-fluoro-3'-deoxy-beta-D-erythropentofura-
                          nosyl)thymidine [MeSH]
 SYNONYMS                 1-(3'-fluoro-3'-deoxy-beta-D-erythropentofura-
                          nosyl)thymine [MeSH]
 PROTOCOL ID NUMBERS      FDA 054A
 PROTOCOL ID NUMBERS      FDA 054B
 PROTOCOL ID NUMBERS      FDA 54C
 SECONDARY SOURCE ID      81-1 [FDA 054A]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: FLT inhibits HIV replication
                          in vitro. By inhibiting reverse transcriptase
                          activity, premature DNA chain termination
                          occurs. Absorption of FLT is rapid, peak
                          plasma concentration (Cmax) was reached in
                          all subjects within 90 minutes. There was up
                          to a three-fold difference in Cmax among
                          subjects at the same dose level. The area
                          under the concentration-time curve (AUC) was
                          less variable, with coefficients of variation
                          ranging from 14% to 21%. Increase in Cmax and
                          AUC were proportional to the increment in
                          dose; mean Cmax's were 234, 529, 1130, and
                          1662 ng/ml for subjects at four dose levels,
                          0.13, 0.3, 0.67 or 1.3 mg/kg. AUC's were 612,
                          1110, 2493 and 5190 ng*hr/ml for each group
                          respectively. The elimination half-life of
                          FLT ranged from 2.5 to 6.3 hours (mean 3.1 to
                          4.3 hours), independent of dose and
                          three-fold longer than the half-life of AZT.
                          In another study the anti-HIV-1 activity of
                          3'-deoxy-3'-fluorothymidine was assessed. Of
                          14 patients enrolled in this study, seven of
                          these had a significant (greater than or
                          equal to eight-fold) decrease in HIV-1 titer
                          isolated from PBMC and/or plasma. Six of
                          seven patients with baseline p24 antigen
                          levels of greater than or equal to 60 pg/ml
                          had a greater than or equal to 50% reduction
                          in antigenemia. [Int Conf AIDS 1992 Jul
                          19-24;8(2): (abstract no. PoB 3025)] [AmFAR
                          Tx Dir April, 1991] [Int Conf AIDS 1991 Jun
                          16-21;7(2): (abstract no W.B. 2114)]
 DISEASES STUDIED/TREATED HIV infection [Int Conf AIDS 1992 Jul
                          19-24;8(2):B91 (abstract no. PoB 3025)]
 CLASSIFICATION CODE      Antiretroviral [Int Conf AIDS 1992 Jul
                          19-24;8(2): (abstract no. PoB 3025)]
 ADVERSE EFFECTS          When FLT was administered in a single dose,
                          no side effects were observed. Hematologic
                          toxicity effects were reported in a multiple
                          dose study to assess hematologic toxicity.
                          [Int Conf AIDS 1992 Jul 19-24;8(1): (abstract
                          no. WeB 1012)] [Int Conf AIDS 1991 Jun
                          16-21;7(2): (abstract no. W.B. 2114)]
 CONTRAINDICATIONS        Contraindicated in patients who are
                          intolerant to zidovudine (AZT), have oral
                          hairy leukoplakia at any time, or are
                          pregnant or breastfeeding. [FDA 054A]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: FLT is a synthesized
                          3'fluor-substituted derivative of
                          2'3'-dideoxythymidine, a pyrimidine
                          nucleoside analogue [AmFAR Tx Dir April,
                          1991]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: FLT is structurally similar
                          to AZT, differing only at the 2' and 3'
                          positions of the ribose; AZT is characterized
                          by an azido group at the 3' position; FLT has
                          a fluoro group at this position [Antimicro
                          Agents Chemother 1990]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C10H13N2O4F1 [Antimicro
                          Agents Chemother 1990 April Mansuri et al.]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Liquid. [Int Conf AIDS 1991 Jun
                          16-21;7(2): (abstract no. W.A. 1041)]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [Int Conf AIDS 1991
                          Jun 16-21;7(2): (abstract no. W.A. 1041)]
 MANUFACTURERS            Lederle
 REFERENCES               Cox SW, Albert J, Ljungdahl-Stahle E, Wahren
                          B. Effect of resistance on combination
                          chemotherapy for human immunodeficiency virus
                          infection. Adv Enzyme Regul. 1993;33:27-36.
 REFERENCES               Clumeck N. Current use of anti-HIV drugs in
                          AIDS. J Antimicrob Chemother. 1993 Jul;32
                          Suppl A:133-8.
 REFERENCES               Flexner C, Polsky B, van der Horst C,
                          Jacobson M, Powderly W, Duncanson F.
                          Relationship between antiretroviral drug
                          exposure and activity in patients receiving
                          3'-deoxy-3'-fluorothymidine (FLT). Int Conf
                          AIDS 1993 Jun 6-11;9(1):489 (abstract no.
                          PO-B26-2123).
 REFERENCES               Polsky B, Barditch-Crovo P, van der Horst C,
                          Flexner C, Raasch R, Duncanson F, Kuye O,
                          Armstron D. Anti-HIV-1 activity of FLT:
                          preliminary results form a clinical trial.
                          Int Conf AIDS. 1992 Jul 19-24;8(2):B91
                          (abstract no. PoB 3025).
 REFERENCES               Barditch-Crovo P, Ganes D, Duncanson F, van
                          der Horst C, Polsky B, Petty B, Faulkner R,
                          Kuye O, Yacobi A, Lietman P, et al. Early
                          markers of hematologic toxicity with FLT
                          therapy. Int Conf AIDS. 1992 Jul
                          19-24;8(1):We47 (abstract no. WeB 1012).
 REFERENCES               Pan XZ, Qiu ZD, Baron PA, Gold JW, Polsky B,
                          Chou TC, Armstrong D. Three-drug synergistic
                          inhibition of HIV-1 replication in vitro by
                          3'-fluoro-3'-deoxythymidine, recombinant
                          soluble CD4, and recombinant
                          interferon-alpha. AIDS Res Hum Retroviruses.
                          1992 May;8(5):589-95.
 REFERENCES               Cox SW, Albert J, Wahlberg J, Uhlen M, Wahren
                          B. Loss of synergistic response to
                          combinations containing AZT in AZT-resistant
                          HIV-1. AIDS Res Hum Retroviruses. 1992
                          Jul;8(7):1229-34.
 REFERENCES               Barditch-Crovo PA, Kornhauser DM, Petty BG,
                          Nerhood LJ, Lietman PS, Faulkner R, Ganes D,
                          Kuye O, Flexner C. Phase I pharmacokinetic
                          evaluation of 3'deoxy-3'-fluorothymidine
                          (FLT), a new potent anti-HIV nucleoside. Int
                          Conf AIDS. 1991 Jun 16-21;7(2):210 (abstract
                          no. W.B. 2114).
 REFERENCES               Lawter JR, Comiskey S, Desai N, Naringrekar
                          V, Tatapudy R. Development of a
                          3'deoxy-3'fluorothymidine (FLT) oral solution
                          dosage form. Int Conf AIDS. 1991 Jun
                          16-21;7(2):102 (abstract no. W.A. 1041).
 REFERENCES               Lundgren B, Bottinger D, Ljungdahl-Stahle E,
                          Norrby E, Stahle L, Wahren B, Oberg B.
                          Antiviral effects of 3'-fluorothymidine and
                          3'-azidothymidine in cynomolgus monkeys
                          infected with simian immunodeficiency virus.
                          J Acquir Immune Defic Syndr.
                          1991;4(5):489-98.
 ENTRY MONTH              9011
 LAST REVISION DATE       951128
 

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