title: Safety and pharmacokinetics of aciclovir in women following release from a silicone elastomer vaginal ring.
abstract: OBJECTIVE
  Systemic aciclovir and its prodrug valaciclovir are effective in treating and reducing recurrences of genital herpes simplex virus (HSV) and reducing transmission. Local aciclovir delivery, if it can achieve and maintain comparable intracellular genital tract levels, may be equally effective in the treatment and suppression of genital HSV. Intravaginal ring (IVR) delivery of aciclovir may provide pre-exposure prophylaxis against HSV acquisition.
  
  
  METHODS
  Tolerability and pharmacokinetics were evaluated in six HIV-negative women with recurrent genital HSV who switched their daily oral valaciclovir suppression to an aciclovir IVR for 7 days (n = 3) or 14 days (n = 3). Blood and cervicovaginal lavage (CVL) were collected after oral and IVR dosing to measure aciclovir concentrations and genital swabs were obtained to quantify HSV shedding by PCR.
  
  
  RESULTS
  The rings were well tolerated. Median plasma aciclovir concentrations were 110.2 ng/mL (IQR, 85.9-233.5) 12-18 h after oral valaciclovir. Little or no drug was detected in plasma following IVR dosing. Median (IQR) CVL aciclovir levels were 127.3 ng/mL (21-660.8) 2 h after oral valaciclovir, 154.4 ng/mL (60.7-327.5) 12-18 h after oral valaciclovir and 438 ng/mL (178.5-618.5) after 7 days and 393 ng/mL (31.6-1615) after 14 days of aciclovir ring use. Median CVL aciclovir levels 2 h after oral dosing were similar to levels observed 7 (P = 0.99) and 14 (P = 0.75) days after ring use. HSV DNA was not detected in genital swabs and there was no significant change in inflammatory mediators.
  
  
  CONCLUSIONS
  This first-in-human study demonstrated that an IVR could safely deliver mucosal levels of aciclovir similar to oral valaciclovir without systemic absorption. More intensive site-specific pharmacokinetic studies are needed to determine whether higher local concentrations are needed to achieve optimal drug distribution within the genital tract.
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. marla.keller@einstein.yu.edu
authors.forename: M J
authors.initials: MJ
authors.lastname: Keller
authors.forename: A M
authors.initials: AM
authors.lastname: Malone
authors.forename: C A
authors.initials: CA
authors.lastname: Carpenter
authors.forename: Y
authors.initials: Y
authors.lastname: Lo
authors.forename: M
authors.initials: M
authors.lastname: Huang
authors.forename: L
authors.initials: L
authors.lastname: Corey
authors.forename: R
authors.initials: R
authors.lastname: Willis
authors.forename: C
authors.initials: C
authors.lastname: Nguyen
authors.forename: S
authors.initials: S
authors.lastname: Kennedy
authors.forename: M
authors.initials: M
authors.lastname: Gunawardana
authors.forename: D
authors.initials: D
authors.lastname: Guerrero
authors.forename: J A
authors.initials: JA
authors.lastname: Moss
authors.forename: M M
authors.initials: MM
authors.lastname: Baum
authors.forename: T J
authors.initials: TJ
authors.lastname: Smith
authors.forename: B C
authors.initials: BC
authors.lastname: Herold
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D003274:Contraceptive Devices, Female / Q000009:adverse effects*; D004337:Drug Carriers / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006558:Herpes Genitalis / Q000188:drug therapy* / Q000517:prevention & control*; D006801:Humans; D008875:Middle Aged; D009092:Mucous Membrane / Q000737:chemistry; D010949:Plasma / Q000737:chemistry; D012826:Silicone Elastomers / Q000008:administration & dosage* / Q000009:adverse effects; D014621:Vagina / Q000737:chemistry
chemical_list: D000998:Antiviral Agents; D004337:Drug Carriers; D012826:Silicone Elastomers; D000212:Acyclovir