Effects of SKF 108922, an HIV-1 protease inhibitor, on retrovirus replication in mice.
Rationally designed synthetic inhibitors of retroviral proteases inhibit the processing of viral polypeptides in cultures of human T lymphocytes infected with human immunodeficiency virus type 1 (HIV-1) and therefore suppress the infectivity of HIV-1 in vitro. We have previously reported the antiviral activity in vitro of HIV-1 protease inhibitors against the C-type retrovirus Rauscher murine leukemia virus (RMuLV) and the lentivirus simian immunodeficiency virus (SIV). The same compounds which blocked the infectivity of HIV-1 also inhibited the infectivity of RMuLV and SIV in vitro. This report extends these findings by testing the antiviral activity of HIV-1 protease inhibitors in vivo in the RMuLV model. RMuLV-infected mice were treated twice a day (bid) with either an active (SKF 108922) or inactive (SKF 109273) compound for fourteen days by the intraperitoneal (i.p.) route. Compared with excipient control, SKF 108922, formulated with hydroxypropyl-beta-cyclodextrin (HPB), reduced virus-induced splenomegaly, viremia, and serum reverse transcriptase (RT) levels, while SKF 109273 was inactive. The HPB vehicle by itself enhanced replication of RMuLV. The effects of changing the formulation and the route of administration were examined. SKF 108922, formulated in HPB, had similar antiviral activity when administered by the i.p. or subcutaneous (SC) routes. However, SKF 108922 administered as a colloidal suspension in cholesterol sulfate (CS) had no detectable antiviral effect. Measurements of the circulating levels of the protease inhibitor in plasma explained this result. Plasma concentrations of SKF 108922 exceeded 1000 nM within 10 min after SC administration of the compound solubilized in HPB, but SKF 108922 was not detected in plasma after SC administration of the same dose formulated with CS. Information on optimal conditions for administering these agents should prove useful in guiding their clinical application Therefore, RMuLV should provide a good model for the preclinical evaluation and development of this class of agents for the treatment of HIV.
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Division of Antiviral Drug Products, Center for Drug Evaluation and Research, HFD-535, US Food and Drug Administration, Rockville, MD 20857, USA.
Ussery
M A
MA
Barney
S
S
Wittrock
R
R
DeMarsh
P
P
Dreyer
G B
GB
Petteway
S R
SR
DalMonte
P
P
Baldoni
J
J
Lambert
D
D
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D000998:Antiviral Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002460:Cell Line; D003505:Cyclodextrins / Q000494:pharmacology; D005260:Female; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014677:Pharmaceutical Vehicles / Q000494:pharmacology; D012194:RNA-Directed DNA Polymerase / Q000097:blood; D011925:Rauscher Virus / Q000187:drug effects*; D012192:Retroviridae Infections / Q000188:drug therapy* / Q000821:virology; D014412:Tumor Virus Infections / Q000188:drug therapy* / Q000821:virology; D047392:beta-Cyclodextrins
D000998:Antiviral Agents; D003505:Cyclodextrins; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D014677:Pharmaceutical Vehicles; D047392:beta-Cyclodextrins; C083669:SK&F 108922; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D012194:RNA-Directed DNA Polymerase