      Document 0131
 DOCN  DRG0131
 UNIQUE IDENTIFIER        DRG-0116
 NAME OF SUBSTANCE        Nevirapine [USAN 1996]
 REGISTRY NUMBER          129618-40-2
 RELATED REGISTRY NUMBER  BI-RG-587
 RELATED REGISTRY NUMBER  BIRG-0587
 STANDARD CHEMICAL NAME   6H-Dipyrido(3,2-b:2',3'-e)(1,4)diazepin-6-one-
                          , 11-cyclopropyl-5,11-dihydro-4-methyl- [USAN
                          1996]
 SYNONYMS                 11-Cyclopropyl-5,11-dihydro-4-methyl-6H-dipyr-
                          ido(3,2-b:2',3'-4) (1,-4)diazepin-6-one
                          [MeSH]
 SYNONYMS                 6,11-dihydro-11-cyclopropyl-4-methyldipyrido(-
                          2,3-b,2',3'-e)(1,4,)-diazepin-6-one [MeSH]
 SYNONYMS                 Viramune [Boehringer Ingelheim
                          Pharmaceuticals; April 8, 1996]
 SYNONYMS                 BIRG-587 [Boehringer Ingelheim
                          Pharmaceuticals; April 8, 1996]
 PROTOCOL ID NUMBERS      NIAID ACTG 164
 PROTOCOL ID NUMBERS      NIAID ACTG 168
 PROTOCOL ID NUMBERS      NIAID ACTG 165
 PROTOCOL ID NUMBERS      NIAID ACTG 208
 PROTOCOL ID NUMBERS      FDA 200B
 PROTOCOL ID NUMBERS      FDA 200C
 PROTOCOL ID NUMBERS      NCI 93 C-192
 PROTOCOL ID NUMBERS      NIAID ACTG 180
 PROTOCOL ID NUMBERS      NIAID ACTG 193A
 PROTOCOL ID NUMBERS      NIAID ACTG 244
 PROTOCOL ID NUMBERS      NIAID ACTG 241
 PROTOCOL ID NUMBERS      NIAID ACTG 245
 PROTOCOL ID NUMBERS      NIAID ACTG 250
 PROTOCOL ID NUMBERS      FDA 229C
 SECONDARY SOURCE ID      DRG
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Selective noncompetitive
                          inhibitor of HIV-1 reverse transcriptase:
                          appears to bind to RT-1 at the same site as
                          the nonnucleoside TIBO derivatives. HIV-1
                          resistance to nevirapine emerges after
                          passage in cell culture in the presence of
                          the drug. Resistance is conferred by a single
                          mutation (tyrosine(181) to cysteine). These
                          strains are cross-resistant with other
                          non-nucleoside reverse transcriptase
                          inhibitors, but not nucleoside-analog reverse
                          transcriptase inhibitors. Investigation of
                          the pharmacokinetic properties of nevirapine
                          was performed following single-dose
                          administration of the drug to 21
                          HIV-1-infected individuals. Different groups
                          of three subjects each were given one of
                          seven dose levels (2.5 to 400 mg) in
                          sequential order, starting with the lowest
                          dose. Each subject received only one dose.
                          Nevirapine was rapidly absorbed at all doses
                          from a tablet formulation. Peak
                          concentrations in plasma were generally
                          achieved within 90 minutes of dose
                          administration. Secondary peaks were also
                          noted between 3 and 12 hours or between 24
                          and 28 hours, the latter being noted mainly
                          in subjects receiving the doses. After 24
                          hours, concentrations in plasma declined in a
                          log linear fashion. The terminal half-life
                          and mean residence time exceeded 24 hours in
                          all but one subject, indicating a prolonged
                          disposition time in this population. Both
                          peak concentrations in plasma and areas under
                          the plasma concentration-time curve appeared
                          to be less than proportional at the 400-mg
                          dose level in this small number of subjects.
                          [AmFAR Tx Dir 1995;7(4)] [Antimicrob Agents
                          Chemother 1993 Feb;37(2)] [J Infect Dis 1995
                          Mar;171(3)]
 DISEASES STUDIED/TREATED HIV infection [AmFAR Tx Dir 1995;7(4)]
 CLASSIFICATION CODE      Antiretroviral [AmFAR Tx Dir 1995;7(4)]
 ADVERSE EFFECTS          Rash has been observed at higher doses of
                          nevirapine (400 mg/day and above). Fourteen
                          of 32 patients who received initial therapy
                          with nevirapine 400 mg experienced side
                          effects; 11/14 permanently discontinued
                          treatment as a result (8 rash, one
                          thrombocytopenia, and two fever). Besides
                          rash, dose-related increases in GGT levels
                          have been observed. These were paralleled by
                          increases in alkaline phosphatase, and were
                          not accompanied by increased SGOT or SGPT
                          levels. One patient who received nevirapine
                          600 mg/day had a severe reaction including
                          facial edema and inability to swallow. [AmFAR
                          Tx Dir 1995;7(4)] [J Infect Dis 1995
                          Mar;171(3)]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: A non-nucleoside
                          dipyridodiazepinone derivative [AmFAR Tx Dir
                          1995;7(4)] [J Infect Dis 1995 Mar;171(3)]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C15H14N4O [USAN 1996]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 266.30 [USAN 1996]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [AmFar Tx Dir
                          September 1990] [J Infect Dis 1995
                          Mar;171(3)]
 MANUFACTURERS            Boehringer
 REFERENCES               Havlir D, Cheeseman SH, McLaughlin M, Murphy
                          R, Erice A, Spector SA, Greenough TC,
                          Sullivan JL, Hall D, Myers M, et al.
                          High-dose nevirapine: safety,
                          pharmacokinetics, and antiviral effect in
                          patients with human immunodeficiency virus
                          infection. J Infect Dis. 1995
                          Mar;171(3):537-45.
 REFERENCES               Cheeseman SH, Havlir D, McLaughlin MM,
                          Greenough TC, Sullivan HL, Hall D, Hattox SE,
                          Spector SA, Stein DS, Myers M, et al. Phase
                          I/II evaluation of nevirapine alone and in
                          combination with zidovudine for infection
                          with human immunideficiency virus. J Acquir
                          Immune Defic Syndr Hum Retrovirol. 1995 Feb
                          1;8(2):141-51.
 REFERENCES               Grodeck B. Triple combination superior to
                          double combination. Posit Aware. 1995
                          Jan/Feb:6.
 REFERENCES               Virus sidesteps convergent therapy. Treat
                          Issues. 1995;9(1):6.
 REFERENCES               Richman DD. Resistance, drug failure, and
                          disease progression. AIDS Res Him
                          Retroviruses. 1994 Aug;10(8):901-5.
 REFERENCES               Havlir D. Antiviral activity of nevirapine at
                          400 mg in p24 antigen positive adults. Int
                          Conf AIDS. 1993 Jun 6-11;9(1):69 (abstract
                          no. WS-B26-1).
 REFERENCES               Cheeseman SH, Murphy RL, Saag, MS, Havlir D.
                          Safety of high dose nevirapine (NVP) after
                          200 mg/d lead-in. Int Conf AIDS. 1993 Jun
                          6-11;9(1):487 (abstract no. PO-B26-2109).
 REFERENCES               Loewenthal M, Hall D, de Jong MD. Treatment
                          with nevirapine and zidovudine in
                          antiretroviral naive HIV-1 infected patients.
                          Int Conf AIDS. 1993 Jun 6-11;9(1):485
                          (abstract no. PO-B26-2101).
 REFERENCES               van der Ende ME, Loewenthal M, de Jong MD.
                          Alternating treatment with nevirapine and
                          zidovudine in antiretroviral naive HIV-1
                          infected patients. Int Conf AIDS. 1993 Jun
                          6-11;9(1):485 (abstract no. PO-B26-2100).
 REFERENCES               Sullivan J, Luzuriaga K. Nevirapine activity
                          and emergence of resistant virus in pediatric
                          trials. Int Conf AIDS. 1993 Jun 6-11;9(1):475
                          (abstract no. PO-B26-2042).
 ENTRY MONTH              9106
 LAST REVISION DATE       960529
 

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