Safety and pharmacokinetics of aciclovir in women following release from a silicone elastomer vaginal ring

Marla J. Keller, A. M. Malone, C. A. Carpenter, Yungtai Lo, M. Huang, L. Corey, R. Willis, C. Nguyen, S. Kennedy, M. Gunawardana, D. Guerrero, J. A. Moss, M. M. Baum, T. J. Smith, Betsy Herold

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Objectives: 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.

Original languageEnglish (US)
Article numberdks151
Pages (from-to)2005-2012
Number of pages8
JournalJournal of Antimicrobial Chemotherapy
Volume67
Issue number8
DOIs
StatePublished - Aug 2012

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Female Contraceptive Devices
valacyclovir
Silicone Elastomers
Acyclovir
Pharmacokinetics
Safety
Simplexvirus
Herpes Genitalis
Therapeutic Irrigation
Virus Shedding
Prodrugs
Pharmaceutical Preparations

Keywords

  • Genital herpes
  • Herpes simplex virus
  • Vaginal microbicides

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Safety and pharmacokinetics of aciclovir in women following release from a silicone elastomer vaginal ring. / Keller, Marla J.; Malone, A. M.; Carpenter, C. A.; Lo, Yungtai; Huang, M.; Corey, L.; Willis, R.; Nguyen, C.; Kennedy, S.; Gunawardana, M.; Guerrero, D.; Moss, J. A.; Baum, M. M.; Smith, T. J.; Herold, Betsy.

In: Journal of Antimicrobial Chemotherapy, Vol. 67, No. 8, dks151, 08.2012, p. 2005-2012.

Research output: Contribution to journalArticle

Keller, MJ, Malone, AM, Carpenter, CA, Lo, Y, Huang, M, Corey, L, Willis, R, Nguyen, C, Kennedy, S, Gunawardana, M, Guerrero, D, Moss, JA, Baum, MM, Smith, TJ & Herold, B 2012, 'Safety and pharmacokinetics of aciclovir in women following release from a silicone elastomer vaginal ring', Journal of Antimicrobial Chemotherapy, vol. 67, no. 8, dks151, pp. 2005-2012. https://doi.org/10.1093/jac/dks151
Keller, Marla J. ; Malone, A. M. ; Carpenter, C. A. ; Lo, Yungtai ; Huang, M. ; Corey, L. ; Willis, R. ; Nguyen, C. ; Kennedy, S. ; Gunawardana, M. ; Guerrero, D. ; Moss, J. A. ; Baum, M. M. ; Smith, T. J. ; Herold, Betsy. / Safety and pharmacokinetics of aciclovir in women following release from a silicone elastomer vaginal ring. In: Journal of Antimicrobial Chemotherapy. 2012 ; Vol. 67, No. 8. pp. 2005-2012.
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abstract = "Objectives: 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.",
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AU - Malone, A. M.

AU - Carpenter, C. A.

AU - Lo, Yungtai

AU - Huang, M.

AU - Corey, L.

AU - Willis, R.

AU - Nguyen, C.

AU - Kennedy, S.

AU - Gunawardana, M.

AU - Guerrero, D.

AU - Moss, J. A.

AU - Baum, M. M.

AU - Smith, T. J.

AU - Herold, Betsy

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N2 - Objectives: 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.

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