title: Pharmacokinetics and preliminary safety study of pod-intravaginal rings delivering antiretroviral combinations for HIV prophylaxis in a macaque model.
abstract: Preexposure prophylaxis using oral regimens involving the HIV nucleoside reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) demonstrated efficacy in three clinical trials. Adherence was determined to be a key parameter for success. Incorporation of the TDF-FTC combination into intravaginal rings (IVRs) for sustained mucosal delivery could increase product adherence and efficacy compared with those of oral and vaginal gel formulations. A novel pod-IVR technology capable of delivering multiple drugs is described; this constitutes the first report of an IVR delivering TDF and FTC, as well as a triple-combination IVR delivering TDF, FTC, and the entry inhibitor maraviroc (MVC). The pharmacokinetics and preliminary local safety of the two combination pod-IVRs were evaluated in the pig-tailed macaque model. The devices exhibited sustained release at controlled rates over the 28-day study period. Median steady-state drug levels in vaginal tissues in the TDF-FTC group were 30 μg g(-1) (tenofovir [TFV], in vivo hydrolysis product of TDF) and 500 μg g(-1) (FTC) and in the TDF-FTC-MVC group were 10 μg g(-1) (TFV), 150 μg g(-1) (FTC), and 20 μg g(-1) (MVC). No adverse events were observed, and there were no toxicological findings. Mild-to-moderate increases in inflammatory infiltrates were observed in the vaginal tissues of some animals in both the presence and the absence of the IVRs. The IVRs did not disturb the vaginal microbiota, and levels of proinflammatory cytokines remained stable throughout the study. Pod-IVR candidates based on the TDF-FTC combination have potential for the prevention of vaginal HIV acquisition and merit clinical investigation.
authors.affiliation: Department of Chemistry, Oak Crest Institute of Science, Pasadena, California, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Moss
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Priya
authors.initials: P
authors.lastname: Srinivasan
authors.affiliation: Department of Chemistry, Oak Crest Institute of Science, Pasadena, California, USA Auritec Pharmaceuticals, Inc., Pasadena, California, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Smith
authors.affiliation: Auritec Pharmaceuticals, Inc., Pasadena, California, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Butkyavichene
authors.affiliation: Auritec Pharmaceuticals, Inc., Pasadena, California, USA.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Lopez
authors.affiliation: Department of Chemistry, Oak Crest Institute of Science, Pasadena, California, USA.
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Brooks
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Martin
authors.affiliation: Total Solutions, Inc., Atlanta, Georgia, USA.
authors.forename: Chuong T
authors.initials: CT
authors.lastname: Dinh
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Smith
authors.affiliation: Department of Chemistry, Oak Crest Institute of Science, Pasadena, California, USA m.baum@oak-crest.org.
authors.forename: Marc M
authors.initials: MM
authors.lastname: Baum
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000282:Administration, Intravaginal; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D008251:Macaca; D063065:Organophosphonates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000068698:Tenofovir; D014621:Vagina / Q000187:drug effects / Q000821:virology; D014622:Vaginal Creams, Foams, and Jellies / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D019380:Anti-HIV Agents; D003692:Delayed-Action Preparations; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D014622:Vaginal Creams, Foams, and Jellies; D003841:Deoxycytidine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine