Mechanism of Action
Valacyclovir is a deoxynucleoside analogue DNA polymerase inhibitor. Valacyclovir hydrochloride is rapidly converted to acyclovir, which has demonstrated antiviral activity against HSV types 1 (HSV-1) and 2 (HSV-2) and VZV both in cell culture and in vivo.
Acyclovir is a synthetic purine deoxynucleoside that is phosphorylated intracellularly by the viral encoded thymidine kinase (TK; pUL23) of HSV or VZV into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In biochemical assays, acyclovir triphosphate inhibits replication of α-herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient phosphorylation by the viral TK.
The quantitative relationship between the cell culture susceptibility of herpes viruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (EC50 ), vary greatly depending upon a number of factors. Using plaque-reduction assays, the EC50 values against herpes simplex virus isolates range from 0.09 to 60 microM (0.02 to 13.5 mcg/mL) for HSV-1 and from 0.04 to 44 microM (0.01 to 9.9 mcg/mL) for HSV-2. The EC50 values for acyclovir against most laboratory strains and clinical isolates of VZV range from 0.53 to 48 microM (0.12 to 10.8 mcg/mL). Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean EC50 value of 6 microM (1.35 mcg/mL).
In Cell Culture: Acyclovir-resistant HSV-1, HSV-2, and VZV strains were isolated in cell culture. Acyclovir-resistant HSV and VZV resulted from mutations in the viral thymidine kinase (TK, pUL23) and DNA polymerase (POL; pUL30) genes. Frameshifts were commonly isolated and result in premature truncation of the HSV TK product with consequent decreased susceptibility to acyclovir. Mutations in the viral TK gene may lead to complete loss of TK activity (TK negative), reduced levels of TK activity (TK partial), or alteration in the ability of viral TK to phosphorylate the drug without an equivalent loss in the ability to phosphorylate thymidine (TK altered).
HSV-Infected Patients: Clinical HSV-1 and HSV-2 isolates obtained from patients who failed treatment for their α-herpes virus infections were evaluated for genotypic changes in the TK and POL genes and for phenotypic resistance to acyclovir. HSV isolates with frameshift mutations and resistance-associated substitutions in TK and POL were identified. The possibility of viral resistance to acyclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy.
Cross-resistance has been observed among HSV isolates carrying frameshift mutations and resistance-associated substitutions, which confer reduced susceptibility to penciclovir, famciclovir, and foscarnet.
The data presented below include references to the steady-state acyclovir AUC observed in humans treated with 1 gram of valacyclovir hydrochloride given orally 3 times a day to treat herpes zoster. Plasma drug concentrations in animal studies are expressed as multiples of human exposure to acyclovir [see Clinical Pharmacology (12.3)].
Valacyclovir was noncarcinogenic in lifetime carcinogenicity bioassays at single daily doses (gavage) of valacyclovir giving plasma acyclovir concentrations equivalent to human levels in the mouse bioassay and 1.4 to 2.3 times human levels in the rat bioassay. There was no significant difference in the incidence of tumors between treated and control animals, nor did valacyclovir shorten the latency of tumors.
Valacyclovir was tested in 5 genetic toxicity assays. An Ames assay was negative in the absence or presence of metabolic activation. Also negative were an in vitro cytogenetic study with human lymphocytes and a rat cytogenetic study.
In the mouse lymphoma assay, valacyclovir was not mutagenic in the absence of metabolic activation. In the presence of metabolic activation (76% to 88% conversion to acyclovir), valacyclovir was mutagenic.
Valacyclovir was mutagenic in a mouse micronucleus assay.
Impairment of Fertility
Valacyclovir did not impair fertility or reproduction in male or female rats at acyclovir exposures (AUC) 6 times higher than in humans given the MRHD. Testicular atrophy occurred in male rats (orally dosed for 97 days at 18 times the MRHD) and was reversible.
Two double-blind, placebo-controlled clinical trials were conducted in 1,856 healthy adults and adolescents (aged greater than or equal to 12 years) with a history of recurrent cold sores. Subjects self-initiated therapy at the earliest symptoms and prior to any signs of a cold sore. The majority of subjects initiated treatment within 2 hours of onset of symptoms. Subjects were randomized to valacyclovir hydrochloride 2 grams twice daily on Day 1 followed by placebo on Day 2, valacyclovir hydrochloride 2 grams twice daily on Day 1 followed by 1 gram twice daily on Day 2, or placebo on Days 1 and 2.
The mean duration of cold sore episodes was about 1 day shorter in treated subjects as compared with placebo. The 2-day regimen did not offer additional benefit over the 1-day regimen.
No significant difference was observed between subjects receiving valacyclovir hydrochloride or placebo in the prevention of progression of cold sore lesions beyond the papular stage.
Six hundred forty-three immunocompetent adults with first-episode genital herpes who presented within 72 hours of symptom onset were randomized in a double-blind trial to receive 10 days of valacyclovir hydrochloride 1 gram twice daily (n = 323) or oral acyclovir 200 mg 5 times a day (n = 320). For both treatment groups the median time to lesion healing was 9 days, the median time to cessation of pain was 5 days, and the median time to cessation of viral shedding was 3 days.
Three double-blind trials (2 of them placebo-controlled) in immunocompetent adults with recurrent genital herpes were conducted. Subjects self-initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode.
In 1 trial, subjects were randomized to receive 5 days of treatment with either valacyclovir hydrochloride 500 mg twice daily (n = 360) or placebo (n = 259). The median time to lesion healing was 4 days in the group receiving valacyclovir hydrochloride 500 mg versus 6 days in the placebo group, and the median time to cessation of viral shedding in subjects with at least 1 positive culture (42% of the overall trial population) was 2 days in the group receiving valacyclovir hydrochloride 500 mg versus 4 days in the placebo group. The median time to cessation of pain was 3 days in the group receiving valacyclovir hydrochloride 500 mg versus 4 days in the placebo group. Results supporting efficacy were replicated in a second trial.
In a third trial, subjects were randomized to receive valacyclovir hydrochloride 500 mg twice daily for 5 days (n = 398) or valacyclovir hydrochloride 500 mg twice daily for 3 days (and matching placebo twice daily for 2 additional days) (n = 402). The median time to lesion healing was about 4½ days in both treatment groups. The median time to cessation of pain was about 3 days in both treatment groups.
Two clinical trials were conducted, one in immunocompetent adults and one in HIV-1-infected adults.A double-blind, 12-month, placebo- and active-controlled trial enrolled immunocompetent adults with a history of 6 or more recurrences per year. Outcomes for the overall trial population are shown in Table 5.
|a Includes lost to follow-up, discontinuations due to adverse events, and consent withdrawn.|
|Outcome||6 Months||12 Months|
|Valacyclovir Hydrochloride 1 gram Once Daily (n = 269)||Oral Acyclovir 400 mg Twice Daily (n = 267)||Placebo (n = 134)||Valacyclovir Hydrochloride 1 gram Once Daily (n = 269)||Oral Acyclovir 400 mg Twice Daily (n = 267)||Placebo (n = 134)|
Subjects with 9 or fewer recurrences per year showed comparable results with valacyclovir hydrochloride 500 mg once daily.In a second trial, 293 HIV-1-infected adults on stable antiretroviral therapy with a history of 4 or more recurrences of ano-genital herpes per year were randomized to receive either valacyclovir hydrochloride 500 mg twice daily (n = 194) or matching placebo (n = 99) for 6 months. The median duration of recurrent genital herpes in enrolled subjects was 8 years, and the median number of recurrences in the year prior to enrollment was 5. Overall, the median pretrial HIV-1 RNA was 2.6 log10 copies/mL. Among subjects who received valacyclovir hydrochloride, the pretrial median CD4+ cell count was 336 cells/mm3 ; 11% had less than 100 cells/mm3 , 16% had 100 to 199 cells/mm3 , 42% had 200 to 499 cells/mm3 , and 31% had greater than or equal to 500 cells/mm3. Outcomes for the overall trial population are shown in Table 6.
|a Includes lost to follow-up, discontinuations due to adverse events, and consent withdrawn.|
|Outcome||Valacyclovir Hydrochloride 500 mg Twice Daily (n = 194)||Placebo (n = 99)|
Reduction of Transmission of Genital Herpes A double-blind, placebo-controlled trial to assess transmission of genital herpes was conducted in 1,484 monogamous, heterosexual, immunocompetent adult couples. The couples were discordant for HSV-2 infection. The source partner had a history of 9 or fewer genital herpes episodes per year. Both partners were counseled on safer sex practices and were advised to use condoms throughout the trial period. Source partners were randomized to treatment with either valacyclovir hydrochloride 500 mg once daily or placebo once daily for 8 months. The primary efficacy endpoint was symptomatic acquisition of HSV-2 in susceptible partners. Overall HSV-2 acquisition was defined as symptomatic HSV-2 acquisition and/or HSV-2 seroconversion in susceptible partners. The efficacy results are summarized in Table 7.
|a Results show reductions in risk of 75% (symptomatic HSV-2 acquisition), 50% (HSV-2 seroconversion), and 48% (overall HSV-2 acquisition) with valacyclovir hydrochloride versus placebo. Individual results may vary based on consistency of safer sex practices.|
|Endpoint||Valacyclovir Hydrochloridea (n = 743)||Placebo (n = 741)|
|Symptomatic HSV-2 acquisition||4 (0.5%)||16 (2.2%)|
|HSV-2 seroconversion||12 (1.6%)||24 (3.2%)|
|Overall HSV-2 acquisition||14 (1.9%)||27 (3.6%)|
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