143. Safety and Pharmacokinetics of Acyclovir in Women Following Release from a Silicone Elastomer Vaginal Ring
Session: Oral Abstract Session: Clinical Virology and Treatment
Friday, October 21, 2011: 10:00 AM
Room: 156ABC
Background: 

Systemic acyclovir (ACV) and its prodrug valacyclovir (VCV) are effective in treating and reducing recurrences of genital herpes simplex virus (HSV).  Once-daily oral VCV reduces the risk of genital HSV transmission among heterosexual, HSV-2-discordant couples.   We hypothesize that local ACV delivery, if it can achieve and maintain comparable intracellular genital tract levels, will be equally effective in the treatment and suppression of genital HSV and avoid systemic exposure.  Intravaginal ring (IVR) delivery of ACV may also protect against HSV acquisition.

Methods: 

Silicone rings, similar in size and shape to Estring, were designed to release ACV at a rate of 240 mg/day.  Tolerability, pharmacokinetics and surrogate efficacy were evaluated in 6 women with recurrent genital HSV who switched their daily oral VCV suppression to an ACV IVR for 7 (n=3) or 14 days (n=3).  Blood and cervicovaginal lavage (CVL) was collected after both oral and IVR dosing to measure ACV concentrations.  As a surrogate of pharmacodynamics, the anti-HSV activity in CVL was measured in a plaque assay. 

Results: 

The rings were well tolerated with no adverse events or expulsions.  Plasma ACV levels ranged from 12.6-529 ng/ml at 12 and 24 hours after oral VCV.  Little or no drug was detected (below quantifiable limit 1 ng/ml) in plasma following IVR dosing.  CVL ACV levels ranged from <25-1404 ng/ml after oral VCV and 45-1615 ng/ml at 1, 3, 7, 10 and 14 days after IVR dosing.  There was 0.17-3.59 and 0.78-3.55 log reduction in HSV after oral and IVR dosing, respectively.  Anti-HSV activity in CVL correlated modestly, but significantly with ACV levels (r=0.33, p<.02).

Conclusion: 

This first-in-human study demonstrated that an IVR could safely deliver ACV and achieve at least as good local mucosal levels as oral therapy without systemic absorption.  These findings support further development and study of an ACV IVR.


Subject Category: V. Virology including clinical and basic studies of viral infections, including hepatitis

Marla Keller, MD1, Amanda Malone, PhD2, John Moss, PhD3, Colleen Carpenter, BA1, Anna Lee, BA1, Erin Diament, FNP1, Robyn Willis, BS, GCPharmSc2, Marc Baum, PhD3, Betsy C. Herold, MD, FIDSA1 and Thomas Smith, MD2, (1)Albert Einstein College of Medicine, Bronx, NY, (2)Auritec Pharmaceuticals, Inc, Santa Monica, CA, (3)Oak Crest Institute of Science, Pasadena, CA

Disclosures:

M. Keller, Auritec Pharmaceuticals, Inc: Investigator, Research support

A. Malone, Auritec Pharmaceuticals: Board Member, Employee, Investigator and Shareholder, Research grant

J. Moss, None

C. Carpenter, None

A. Lee, None

E. Diament, None

R. Willis, None

M. Baum, None

B. C. Herold, None

T. Smith, Auritec Pharmaceuticals: Board Member, Investigator and Shareholder, Salary

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