      Document 0038
 DOCN  DRG0038
 UNIQUE IDENTIFIER        DRG-0209
 NAME OF SUBSTANCE        bis-POM PMEA [FDA 232A]
 STANDARD CHEMICAL NAME   9-[2-(bispivaloyloxymethyl)
                          phosphonylmethoxyethyl]-adenine [FDA 232A]
 SYNONYMS                 Bis(pom)PMEA [Antimicrob Agents Chemother
                          1993 Oct;37(10)]
 SYNONYMS                 Bis(pivaloyloxymethyl) PMEA [Antiviral Res
                          1992 Sep;19[3]
 PROTOCOL ID NUMBERS      FDA 232A
 PROTOCOL ID NUMBERS      FDA 232B
 PROTOCOL ID NUMBERS      NCI 95 C-83
 SECONDARY SOURCE ID      GS-0840 [FDA 232A]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: bis-POM PMEA exhibited in
                          vitro antiviral activity against HIV and HCMV
                          that was equipotent with the parent compound,
                          PMEA. Metabolic studies of both compounds
                          suggested a > 100-fold increase in the
                          cellular uptake of the bis-POM derivative and
                          formation of active diphosphorylated
                          metabolite; however, bis-POM derivatives were
                          chemically unstable and highly susceptible to
                          serum-mediated hydrolysis, factors that limit
                          their potential utility for intracellular
                          drug delivery. [Antivital Res 1992
                          Sep;19(3)]; Antimicrob Agents Chemother 1993
                          Oct;37(10)]
 DISEASES STUDIED/TREATED Primary HIV infection [FDA 232A]
 CLASSIFICATION CODE      Antiretrovial [Antiviral Res 1992 Sep;19(3)]
 CONTRAINDICATIONS        Contraindicated in pregnant and lactating
                          women. [FDA 232A]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: The bis(pivaloyloxymethyl)
                          derivative of the nucleoside phosphonate
                          PMEA; ester prodrug of PMEA acetylated with
                          chloromethyl pivalate [Antiviral Res 1992
                          Sep;19(3)] [Antimicrob Agents Chemother 1993
                          Oct;37(10)]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Low aqueous solubility [Pharm Res
                          1994 Jun;11(6)]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Granules. [FDA 232A]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [FDA 232A]
 MANUFACTURERS            Gilead Sciences Inc
 REFERENCES               Robbins BL, Connelly MC, Marshall DR,
                          Srinivas RV, Fridland A. A human T lymphoid
                          cell variant resistant to the acyclic
                          nucleoside phosphonate
                          9-(2-phosphonylmethoxyethyl)adenine shows a
                          unique combination of a phosphorylation
                          defect and increased efflux of the agent. Mol
                          Pharmacol. 1995 Feb;47(2):391-7.
 REFERENCES               Barditch-Crovo PA, Cundy KC, Wachsman M,
                          Toole J, Burgee H, Ebeling D. Pharmacokinetic
                          profile of 9-[2-(bispivaloyloxy-methyl)
                          phosphonylmethoxy]adenine (bis-POM PMEA), an
                          orally bioavailable prodrug of the antiviral
                          nucleotide, PMEA. Natl Conf Hum Retroviruses
                          Relat Infect (2nd). 1995 Jan 29-Feb 2;:145.
 REFERENCES               Starrett JE Jr, Tortolani DR, Russell J,
                          Hitchcock MJ, Whiterock V, Martin JC, Mansuri
                          MM. Synthesis, oral bioavailability
                          determination, and in vitro evaluation of
                          prodrugs of the antiviral agent
                          9-[2-(phosphonomethoxy)ethyl]adenine (PMEA).
                          J Med Chem. 1994 Jun 10;37(12):1857-64.
 REFERENCES               Cundy KC, Fishback JA, Shaw JP, Lee ML, Soike
                          KF, Visor GC, Lee WA. Oral bioavailability of
                          the antiretroviral agent
                          9-(2-phosphonylmethoxyethyl)adenine (PMEA)
                          from three formulations of the prodrug
                          bis(pivaloyloxymethyl)-PMEA in fasted male
                          cynomolgus monkeys. Pharm Res. 1994
                          Jun;11(6):839-43.
 REFERENCES               Balzarini J. Metabolism and mechanism of
                          antiretroviral action of purine and
                          pyrimidine derivatives. Pharm World Sci. 1994
                          Apr 15;16(2):113-26.
 REFERENCES               Hitchcock MJ, Lacy SA. Bis-pivaloyloxymethyl
                          PMEA as an oral prodrug of PMEA: pilot
                          toxicity evaluation in rats. Natl Conf Hum
                          Retroviruses Relat Infect (1st). 1993 Dec
                          12-16;159.
 REFERENCES               Puech F, Gosselin G, Lefebvre I, Pompon A,
                          Aubertin AM, Kirn A, Imbach JL. Intracellular
                          delivery of nucleoside monophosphates through
                          a reductase-mediated activation process.
                          Antiviral Res. 1993 Oct;22(2-3):155-74.
 REFERENCES               Srinivas RV, Robbins BL, Connelly MC, Gong
                          YF, Bischofberger N, Fridland A. Megabolism
                          and in vitro antiretroviral activities of
                          bis(pivaloyloxmethyl) prodrugs of acyclic
                          nucleoside phosphonates. Antimicrob Agents
                          Chemother. 1993 Oct;37(10):2247-50.
 REFERENCES               Starrett JE Jr, Tortolani DR, Hitchcock MJ,
                          Martin JC, Mansuri MM. Synthesis and in vitro
                          evaluation of a phosphonate prodrug:
                          bis(pivaloyloxymethyl)
                          9-(2-phosphonylmethoxyethyl)adenine.
                          Antiviral Res. 1992 Sep;19(3):267-73.
 ENTRY MONTH              9405
 LAST REVISION DATE       960424
 

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