title: Simultaneous delivery of tenofovir and acyclovir via an intravaginal ring.
abstract: Vaginal microbicides may play an important role in protecting women from HIV infection. A strong synergy between HSV and HIV has been observed, and epidemiological studies demonstrate that HSV infection increases the risk of HIV acquisition. Incorporation of the antiretroviral tenofovir (TFV) along with the antiherpetic acyclovir (ACV) into combination intravaginal rings (IVRs) for sustained mucosal delivery of both compounds could lead to increased microbicide product adherence and efficacy compared with conventional vaginal formulations. A novel, dual-protection "pod IVR" platform developed in-house and delivering ACV and TFV was evaluated in rabbit and sheep models. The devices were safe and exhibited sustained release of both drugs independently and at controlled rates over the 28-day studies. Daily release rates were estimated based on residual drug content of the used devices: rabbits, 343 ± 335 μg day(-1) (ACV) and 321 ± 207 μg day(-1) (TFV); sheep, 174 ± 14 μg day(-1) (ACV) and 185 ± 34 μg day(-1) (TFV). Mean drug levels in sheep vaginal samples were as follows: secretions, 5.25 ± 7.31 μg ml(-1) (ACV) and 20.6 ± 16.2 μg ml(-1) (TFV); cervicovaginal lavage fluid, 118 ± 113 ng ml(-1) (ACV) and 191 ± 125 ng ml(-1) (TFV); tissue, 173 ng g(-1) (ACV) and 93 ng g(-1) (TFV). An in vitro-in vivo correlation was established for both drugs and will allow the development of future formulations delivering target levels for prophylaxis and therapy. These data suggest that the IVR based on the pod design has potential in the prevention of transmission of HIV-1 and other sexually transmitted pathogens.
authors: Department of Chemistry, Oak Crest Institute of Science, Pasadena, California, USA.
authors: John A
authors: JA
authors: Moss
authors: Amanda M
authors: AM
authors: Malone
authors: Thomas J
authors: TJ
authors: Smith
authors: Sean
authors: S
authors: Kennedy
authors: Etana
authors: E
authors: Kopin
authors: Cali
authors: C
authors: Nguyen
authors: Josh
authors: J
authors: Gilman
authors: Irina
authors: I
authors: Butkyavichene
authors: Kathleen L
authors: KL
authors: Vincent
authors: Massoud
authors: M
authors: Motamedi
authors: David R
authors: DR
authors: Friend
authors: Meredith R
authors: MR
authors: Clark
authors: Marc M
authors: MM
authors: Baum
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; 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; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004338:Drug Combinations; D016503:Drug Delivery Systems; D004867:Equipment Design; D005260:Female; D015658:HIV Infections / Q000517:prevention & control* / Q000635:transmission / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006558:Herpes Genitalis / Q000517:prevention & control* / Q000635:transmission / Q000821:virology; D018258:Herpesvirus 2, Human / Q000187:drug effects*; D006801:Humans; D063065:Organophosphonates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011817:Rabbits; D015229:Sexually Transmitted Diseases, Viral / Q000517:prevention & control / Q000635:transmission / Q000821:virology; D000068698:Tenofovir; D016896:Treatment Outcome
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D063065:Organophosphonates; D000068698:Tenofovir; D000225:Adenine; D000212:Acyclovir