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PubMed1996

Pharmacokinetics and safety of multiple-dose valaciclovir in geriatric volunteers with and without concomitant diuretic therapy.

A randomized, double-blind study was conducted to evaluate the safety and pharmacokinetics of acyclovir following multiple-dose oral administration of valaciclovir (three times a day for 8 days) in geriatric volunteers (65 to 83 years of age). Pharmacokinetic evaluation was performed for three groups: normotensive subjects given 500-mg doses of valaciclovir (n = 11), normotensive subjects given, 1,000-mg doses of valaciclovir (n = 9), and thiazide diuretic-treated hypertensive subjects given 500-mg doses of valaciclovir (n = 9). Valaciclovir, the l-valyl ester of acylclovir, was rapidly absorbed and converted to acyclovir, with plasma valaciclovir concentrations generally undetectable or < or = 0.4 microgram/ml. The peak concentration of drug in plasma (Cmax) for acyclovir occurred at 1 to 2 h, and the half-life of acyclovir was 3 to 4 h in all three elderly groups. The Cmax and area under the concentration-time curve from 0 h to infinity (AUC0-infinity) values of acyclovir obtained on days 1 and 8 indicated no unexpected accumulation at steady state. The steady-state acyclovir Cmax (4.30 and 5.98 micrograms/ml) and daily AUC0-infinity (44 and 74 h.micrograms/ml) following dosing of valaciclovir (500 and 1,000 mg) three times a day were two to three times greater than those expected after high-dose oral acyclovir treatment (800 mg, five times daily). There were no valaciclovir-related changes or abnormalities in safety parameters and no reports of serious adverse experiences in these elderly volunteers. The plasma acyclovir concentration-time curves for the hypertensive and normotensive (500-mg valaciclovir treatment) elderly groups were almost superimposable, and acyclovir pharmacokinetic parameters for the two groups were not significantly different, indicating that concomitant thiazide diuretics do not alter acyclovir pharmacokinetics following valaciclovir dosing in the elderly. Compared with historical data for younger volunteers (creatinine clearance [CLCR] > 75 ml/min/1.73 m2), the elderly subjects (CLCR = 40 to 65 ml/min/1.73 m2) showed higher (approximately 15 to 20%) mean Cmaxs and higher (approximately 30 to 50%) mean AUC(0-infinity)s of acyclovir (P < 0.01), which were consistent with age-related decreases in CLCR. The increased acyclovir exposure from valaciclovir dosing will permit reduced dosing frequency and may result in improved efficacy in the management of herpesvirus diseases.

Acyclovir↗
PubMed1996

Comparison of effects of famciclovir and valaciclovir on pathogenesis of herpes simplex virus type 2 in a murine infection model.

The effects of famciclovir (FCV) and valaciclovir (VACV) were compared in a cutaneous infection model for herpes simplex virus type 2 (HSV-2). The compounds were administered orally from day 1 to day 5 postinfection. Both compounds reduced local inflammation and virus replication in the skin. FCV markedly reduced mortality and virus replication in the nervous system. On the cessation of therapy after 5 days, when the levels of infectious virus in the tissues were reduced to below the level of detection, there followed a rebound of virus replication in the ganglia and brain stems of mice that had been treated with VACV. The recurrence of infection in the brain stem occurred on three separate occasions. No such recurrences were observed following FCV treatment. When ganglia were explanted from survivors 6 weeks later, latent virus was shown to be reactivated in all 10 of 10 control, untreated mice. The number of mice whose ganglia yielded virus was reduced to 60% in mice that had been treated with VACV, whereas no mice that had been treated with FCV had evidence of latent infection by this test.

2-Aminopurine↗
PubMed1998

Famciclovir and valaciclovir differ in the prevention of herpes simplex virus type 1 latency in mice: a quantitative study.

Famciclovir (FCV) and valaciclovir (VACV) have previously been shown to be potent inhibitors of herpes simplex virus type 1 (HSV-1) in a murine cutaneous model. In the present study, mice were inoculated in the skin of the left ear pinna with herpes simplex virus (HSV) type 1. Antiviral therapy was started on different days postinoculation (p.i.), terminating at the end of day 10 p.i. The compounds were administered twice daily by oral gavage at 50 mg/kg of body weight/dose. Mice were sampled on day 5 p.i., during the acute phase of the infection, and the titers of infectious virus in the target tissues (ear, brain stem, and trigeminal ganglia) were determined. At 2 to 3 months p.i., the ipsilateral and contralateral trigeminal and cervical dorsal root ganglia were explanted, and four different methods were used to detect latent HSV. The methods were (i) conventional explant culture for 5 days followed by homogenization, (ii) long-term culture (up to 73 days) of whole ganglia, followed by homogenization, (iii) dissociation by enzymatic disaggregation and an infectious center assay, and (iv) in situ hybridization to detect latency-associated transcripts (LATs). The conventional explant culture method was the least sensitive method, while in situ staining for LAT was the most sensitive, and all mice, including those treated from early times with FCV, were shown to be latently infected. Significantly less latent virus was detected by all four methods, however, in ganglia obtained from mice that had been treated with FCV in comparison with the amount detected in ganglia from mice that had been treated with VACV. However, in no case was latency completely eliminated.

2-Aminopurine↗
PubMed2000

Bioavailability of aciclovir after oral administration of aciclovir and its prodrug valaciclovir to patients with leukopenia after chemotherapy.

The median bioavailabilities of aciclovir after administration of aciclovir and its prodrug valaciclovir were 21.5 and 70.1%, respectively, in 12 patients with malignant hematological diseases with leukopenia after chemotherapy. The interindividual variations of the bioavailability were 48.5 and 21.0% after administration of aciclovir and valaciclovir, respectively. Neither the bioavailability nor the interindividual variation of area under the concentration-time curve of oral aciclovir or valaciclovir differed from that reported in healthy volunteers.

Acyclovir↗
PubMed2000

Persistence of infectious herpes simplex virus type 2 in the nervous system in mice after antiviral chemotherapy.

Young adult mice were inoculated with herpes simplex virus type 2 (HSV-2) in the ear pinna. A relatively severe infection resulted, and 45% of the mice died by 11 days postinfection. Therapy at 1 mg/ml by means of the drinking water with either famciclovir for periods of 5 or 10 days or valaciclovir for 5, 10, 15, or 20 days decreased clinical signs and reduced mortality to 15% or less. Throughout a period of 27 days, mice were tested daily for the presence of infectious virus in the ear pinna, brain stem, and ipsilateral trigeminal ganglia. Virus was cleared from these tissues in surviving, untreated animals by 12 days postinfection, and no infectious virus was detected subsequently in any tissue. Furthermore, no infectious virus was detected after day 9 in mice that had been treated with famciclovir. In mice that had received valaciclovir therapy, however, infectious virus was repeatedly detected in the trigeminal ganglia and brain stem tissue samples up to 7 days after treatment was discontinued. To date, no specific mechanism to account for these results has been discovered; however, possible mechanisms for the persistence of potentially infectious virus in neural tissue of treated mice are discussed.

2-Aminopurine↗
PubMed2002

Multiple interactions of cimetidine and probenecid with valaciclovir and its metabolite acyclovir.

The effects of probenecid and cimetidine on the pharmacokinetics of valaciclovir and its metabolite acyclovir have been investigated. Twelve healthy male volunteers participated in this open single-dose study with a four-way-crossover randomized and balanced design. At the first of four administrations, volunteers in four groups received 1 g of valaciclovir alone, valaciclovir with 1 g of probenecid, valaciclovir with 800 mg of cimetidine, or valaciclovir with a combination of probenecid and cimetidine. At three subsequent administrations, drug regimens were alternated among groups so that each group received each regimen. Probenecid and cimetidine increased the mean maximum concentrations in serum (C(max)) of valaciclovir by 23 and 53% and the areas under the concentration-time curves (AUC) for valaciclovir by 22 and 73%, respectively; probenecid and cimetidine also increased the mean acyclovir C(max) by 22 and 8% and its AUC by 48 and 27%, respectively. The combination had a greater effect than either drug alone. Their effects may be due to competitive inhibition of membrane transport of valaciclovir and acyclovir in the liver and kidney. Neither cimetidine nor probenecid affected the absorption of valaciclovir. Both probe drugs reduced the rate of valaciclovir metabolism but not its extent. These pharmacokinetic modifications did not affect the tolerability of valaciclovir.

Acyclovir↗
PubMed2005

Susceptibilities of several clinical varicella-zoster virus (VZV) isolates and drug-resistant VZV strains to bicyclic furano pyrimidine nucleosides.

Varicella-zoster virus (VZV) is responsible for primary infections as well as reactivations after latency in the dorsal root ganglia. The treatment of such infections is mandatory for immunocompromised patients and highly recommended for elderly patients with herpes zoster infections (also called zona or shingles). The treatment of choice is presently based on four molecules, acyclovir (ACV), valaciclovir, famciclovir, and (in Europe) brivudine (BVDU). We present here our data on the antiviral activity of a new class of potent and selective anti-VZV compounds, bicylic pyrimidine nucleoside analogues (BCNAs), against a broad variety of clinical isolates and different drug-resistant virus strains. The results show that the BCNAs are far more potent inhibitors than ACV and BVDU against clinical VZV isolates as well as the VZV reference strains Oka and YS. The BCNAs were not active against ACV- and BVDU-resistant VZV strains bearing mutations in the viral thymidine kinase gene but kept their inhibitory potential against virus strains with mutations in the VZV DNA polymerase gene. Mutant virus strains selected in the presence of the BCNAs were solely cross-resistant to drugs, such as ACV and BVDU, that depend for their antiviral action on metabolic activation by the viral thymidine kinase.

2-Aminopurine↗
PubMed2005

Early selection of a new UL97 mutant with a severe defect of ganciclovir phosphorylation after valaciclovir prophylaxis and short-term ganciclovir therapy in a renal transplant recipient.

We describe the emergence of a new ganciclovir resistance mutation in the UL97 gene of human cytomegalovirus, deletion of codon 601, after valaciclovir and short-term ganciclovir therapy following kidney transplantation. Its role in ganciclovir resistance was supported by decreased ganciclovir phosphorylation in a recombinant vaccinia virus system.

Acyclovir↗
PubMed1997

Valaciclovir for the suppression of recurrent genital HSV infection: a placebo controlled study of once daily therapy. International Valaciclovir HSV Study Group.

OBJECTIVE: To determine the efficacy and safety of once daily valaciclovir for the suppression of recurrent genital herpes simplex virus (HSV) infection in immunocompetent patients. METHODS: 382 otherwise healthy patients with a history of frequently recurring genital HSV infection (eight recurrences per year) were randomly allocated to receive either oral valaciclovir (500 mg once daily) or placebo (3:1 ratio) for 16 weeks or until the first genital HSV recurrence, whichever occurred first. Patients were clinically assessed at regular intervals and also if they experienced a recurrence. Safety was evaluated through adverse experience reporting and monitoring of haematology and biochemistry variables. On completion of the double blind phase, patients were eligible for follow up to a maximum of 48 weeks' treatment with open label valaciclovir (500 mg once daily) for further safety monitoring. The results from the double blind phase of the study are reported here. RESULTS: A significant difference was detected between valaciclovir and placebo in the time to first recurrence of genital HSV infection. The hazard ratio [95% confidence interval] for valaciclovir v placebo was 0.155 [0.112, 0.214], p < 0.0001. Valaciclovir prevented or delayed 85% of the recurrences that would have occurred with placebo. After 16 weeks (day 112) with treatment, 69% of patients receiving valaciclovir were recurrence free compared with only 9.5% of patients assigned to placebo. The safety profiles of valaciclovir and placebo were comparable, with adverse experiences being infrequent and generally mild. CONCLUSION: This study has demonstrated that once daily valaciclovir (500 mg), is highly effective and well tolerated for the suppression of recurrent genital HSV infection. Once daily dosing with valaciclovir provides a more convenient dosing regimen than the more frequent aciclovir regimens.

Acyclovir↗
PubMed1997

Valaciclovir versus aciclovir in patient initiated treatment of recurrent genital herpes: a randomised, double blind clinical trial. International Valaciclovir HSV Study Group.

OBJECTIVE: To compare the efficacy and safety of twice daily valaciclovir with five times daily aciclovir in the treatment of an episode of recurrent genital herpes simplex virus (HSV) infection in immunocompetent individuals. METHODS: 739 patients with a history of recurrent genital HSV infection received either oral valaciclovir (500 mg twice daily) or aciclovir (200 mg five times daily) for 5-days for treatment of their next recurrent episode in a controlled, randomised, double blind trial. Patients self initiated therapy at the first signs and/or symptoms of the HSV recurrence, then were assessed in clinic on five occasions over 7 days, and twice weekly thereafter until lesions had healed. Safety was evaluated through adverse experience reports and haematology and biochemistry monitoring. RESULTS: No significant differences were detected between valaciclovir and aciclovir for the primary endpoint, the duration of all signs and symptoms which included lesion healing and pain/discomfort. The hazard ratio [95% confidence interval] for valaciclovir v aciclovir was 0.93 [0.79, 1.08]. Lesion healing time was similar in each treatment group (hazard ratio valaciclovir v aciclovir 0.96 [0.80, 1.14]). The odds ratio of valaciclovir v aciclovir in preventing the development of vesicular/ulcerative lesions was 1.08 [0.82, 1.42]. Percentages of patients in whom all HSV cultures were negative were similar in the valaciclovir and aciclovir groups at 59% and 54% respectively; for patients having equal to or more than one positive culture result after treatment initiation, cessation of virus shedding was similarly rapid for the two treatments (hazard ratio 0.98 [0.75, 1.27]). The safety profiles of valaciclovir and aciclovir were comparable with adverse experiences being infrequent and generally mild. CONCLUSION: This study has demonstrated that valaciclovir 500 mg twice daily is equivalent in efficacy to aciclovir 200 mg five times daily as episodic treatment of recurrent genital HSV infection. Valaciclovir maintains the established efficacy and safety of aciclovir but offers a much more convenient twice daily dosing regimen.

Acyclovir↗
PubMed1999

Impact of suppressive antiviral therapy on the health related quality of life of patients with recurrent genital herpes infection.

OBJECTIVE: To investigate whether suppressive antiviral therapy improves health related quality of life in patients with recurrent genital herpes. METHODS: Health related quality of life was measured using the disease specific recurrent genital herpes quality of life questionnaire (RGHQoL) as part of a randomized, double blind, 52 week, placebo controlled, dose ranging study of once and twice daily valaciclovir or aciclovir for the suppression of recurrent genital herpes in patients with six or more recurrences per year. RESULTS: Of 1479 participants, 1349 patients completed the baseline questionnaire. There were no significant baseline differences in RGHQoL score between any of the treatment groups. After 3 months there were significantly greater improvements in mean RGHQoL scores for all active treatment groups compared with placebo (p < 0.05). Mean RGHQoL score improvements from baseline remained significantly higher in the active treatment groups than in the placebo group after 6 and 12 months, indicating that the improved health related quality of life in patients receiving suppressive antiviral therapy was sustained over a prolonged period of time. CONCLUSION: Suppressive antiviral therapy is an effective strategy for improving the quality of life of patients with recurrent genital herpes. These improvements in quality of life are sustained over time, thus enhancing the clinical benefit in the long term management of this condition.

Acyclovir↗
PubMed2002

Aborted genital herpes simplex virus lesions: findings from a randomised controlled trial with valaciclovir.

OBJECTIVES: In prospective trials, episodic valaciclovir significantly increased the chance of preventing or aborting the development of painful vesicular genital herpes simplex virus (HSV) lesions compared with placebo. We explored the clinical outcome of aborted lesions and its association with early treatment in a study designed to compare 3 and 5 days' treatment with valaciclovir. METHODS: In a randomised controlled trial, valaciclovir 500 mg twice daily for 3 or 5 days was initiated at the first symptoms of a genital herpes outbreak. The primary end point was length of episode with pain, HSV shedding, and aborted lesions secondary end points. The effect of time from symptom recognition to treatment initiation on aborted lesions was assessed in a post hoc analysis. RESULTS: In 531 patients, no differences were observed between 3 and 5 days' treatment in episode duration (median 4.7 v 4.6 days), loss of pain/discomfort (2.8 v 3.0 days), or lesion healing (4.9 v 4.5 days). Vesicular lesions were aborted in 27% of patients treated for 3 days v 21% of patients receiving valaciclovir for 5 days. The odds of achieving an aborted episode were 1.93 (95% CI: 1.28 to 2.90) times higher for those initiating treatment with valaciclovir within 6 hours of first sign or symptom. CONCLUSIONS: There was no difference between 3 and 5 days' treatment in reducing episode duration or lesion abortion. Prompt treatment with valaciclovir can abort genital HSV reactivation episodes, preventing a vesicular outbreak. Maximum treatment benefit depends on prompt therapy after recognition of symptoms.

Acyclovir↗