title: Pharmacokinetic and Pharmacodynamic Evaluation following Vaginal Application of IQB3002, a Dual-Chamber Microbicide Gel Containing the Nonnucleoside Reverse Transcriptase Inhibitor IQP-0528 in Rhesus Macaques.
abstract: We evaluated the in vivo pharmacokinetics and used a complementary ex vivo coculture assay to determine the pharmacodynamics of IQB3002 gel containing 1% IQP-0528, a nonnucleoside reverse transcriptase inhibitor (NNRTI), in rhesus macaques (RM). The gel (1.5 ml) was applied vaginally to 6 simian-human immunodeficiency (SHIV)-positive female RM. Blood, vaginal fluids, and rectal fluids were collected at 0, 1, 2, and 4 h. RM were euthanized at 4 h, and vaginal, cervical, rectal, and regional lymph node tissues were harvested. Anti-human immunodeficiency virus (HIV) activity was evaluated ex vivo by coculturing fresh or frozen vaginal tissues with activated human peripheral blood mononuclear cells (PBMCs) and measuring the p24 levels for 10 days after an HIV-1Ba-L challenge. The median levels of IQP-0528, determined using liquid chromatography-tandem mass spectroscopy (LC-MS/MS) methods, were between 10(4) and 10(5) ng/g in vaginal and cervical tissue, between 10(3) and 10(4) ng/g in rectal tissues, and between 10(5) and 10(7) ng/ml in vaginal fluids over the 4-h period. The vaginal tissues protected the cocultured PBMCs from HIV-1 infection ex vivo, with a viral inhibition range of 81 to 100% in fresh and frozen tissues that were proximal, medial, and distal relative to the cervix. No viral inhibition was detected in untreated baseline tissues. Collectively, the median drug levels observed were 5 to 7 logs higher than the in vitro 50% effective concentration (EC50) range (0.21 ng/ml to 1.29 ng/ml), suggesting that 1.5 ml of the gel delivers IQP-0528 throughout the RM vaginal compartment at levels that are highly inhibitory to HIV-1. Importantly, antiviral activity was observed in both fresh and frozen vaginal tissues, broadening the scope of the ex vivo coculture model for future NNRTI efficacy studies.
authors.affiliation: LifeSource Biomedical LLC, Moffett Field, California, USA.
authors.forename: Lara E
authors.initials: LE
authors.lastname: Pereira
authors.affiliation: Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Pedro M M
authors.initials: PM
authors.lastname: Mesquita
authors.affiliation: ImQuest BioSciences, Frederick, Maryland, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Ham
authors.affiliation: Anyar Inc., Fort Walton Beach, Florida, USA.
authors.forename: Tyana
authors.initials: T
authors.lastname: Singletary
authors.affiliation: Total Solutions, Inc., Madison, Alabama, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Deyounks
authors.affiliation: Centers for Disease Control and Prevention, Division of HIV/AIDS Prevention, Atlanta, Georgia, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Martin
authors.affiliation: Centers for Disease Control and Prevention, Division of HIV/AIDS Prevention, Atlanta, Georgia, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: McNicholl
authors.affiliation: ImQuest BioSciences, Frederick, Maryland, USA.
authors.forename: Karen W
authors.initials: KW
authors.lastname: Buckheit
authors.affiliation: ImQuest BioSciences, Frederick, Maryland, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Buckheit
authors.affiliation: Centers for Disease Control and Prevention, Division of HIV/AIDS Prevention, Atlanta, Georgia, USA ajo9@cdc.gov.
authors.forename: James M
authors.initials: JM
authors.lastname: Smith
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D018920:Coculture Techniques; D015925:Cryopreservation; D005260:Female; D015658:HIV Infections / Q000517:prevention & control; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D008253:Macaca mulatta; D010880:Piperidines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy
chemical_list: C418003:IQB 9302; C573126:IQP-0528; D010880:Piperidines; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors