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PubMed1996

Differential effects of famciclovir and valaciclovir on the pathogenesis of herpes simplex virus in a murine infection model including reactivation from latency.

The ability of famciclovir and valaciclovir to affect the establishment and maintenance of latency in mice with a cutaneous herpes simplex type 1 (HSV-1) infection was examined. Mice were treated via drinking water starting at various times between days 1 and 5 and terminating on day 10 after inoculation. Clinical signs and viral replication in the target tissues were monitored. Three to four months later, trigeminal and dorsal root ganglia were explanted from groups of 16 mice and examined for latent virus by cocultivation. The two compounds differed in their effects on the acute neural infection, and ganglia explanted from famciclovir-treated mice were markedly reduced in their ability to reactivate virus, although neither drug affected latency if treatment was delayed for several months. The difference between the compounds is likely to reflect differences in the metabolism of their respective products, penciclovir and acyclovir, in infected neurons.

2-Aminopurine↗
PubMed1996

Lack of interaction between valaciclovir, the L-valyl ester of acyclovir, and Maalox antacid.

Valaciclovir is rapidly and extensively converted to acyclovir. In this study we investigated the potential interaction between oral valaciclovir and Maalox. On each of three occasions 18 healthy volunteers received a single oral dose of 1000 mg valaciclovir, or 30 mL Maalox 65 min after valaciclovir administration, or 30 mL Maalox 30 min before valaciclovir. Acyclovir plasma concentrations and pharmacokinetic parameters were not significantly affected by administration of Maalox before or after valaciclovir. Therefore, there is no need for restriction of valaciclovir dosing in patients receiving antacid medication.

Acyclovir↗
PubMed1994

Phase I trial of valaciclovir, the L-valyl ester of acyclovir, in patients with advanced human immunodeficiency virus disease.

Valaciclovir, the L-valyl ester of acyclovir, is rapidly and extensively converted in humans to acyclovir after oral administration by first-pass metabolism. A phase I study was conducted in two cohorts of volunteers with advanced human immunodeficiency virus (HIV) disease (absolute CD4 lymphocyte count of < 150 cells per microliters) who received oral valaciclovir at dosages of 1,000 or 2,000 mg four times daily for 30 days. All patients were clinically stable without any changes in underlying HIV-related medications for > or = 6 weeks prior to entry in study; these medications were continued throughout the study. Multiple-dose administration of valaciclovir showed a generally favorable safety profile. Nausea, vomiting, diarrhea, and abdominal pain each were reported in < or = 31% of the patients; of these symptoms, only one episode of diarrhea was considered causally related to valaciclovir exposure. Four patients developed neutropenia (two at each dose level) which was not clinically significant. There were no renal or neurologic adverse events. Valaciclovir was rapidly absorbed and converted to acyclovir, with plasma valaciclovir levels generally undetectable or levels of < or = 0.4 microgram/ml. After 3 h postdosing, valaciclovir was not detectable in plasma. Acyclovir was measurable in plasma as early as 15 min following valaciclovir dosing, and plasma concentrations of acyclovir greatly exceeded those of valaciclovir. The mean values for the maximum concentration of drug in plasma, time to maximum concentration of drug in plasma, area under the concentration-time curve from 0 h to infinity, and apparent half-life of acyclovir obtained after single- and multiple-dose valaciclovir administration in HIV-infected patients were similar to those reported in normal healthy volunteers. The time to maximum concentration in serum and half-life of acyclovir after valaciclovir administration were approximately 2 and 3 h, respectively, which were similar to those reported after oral administration of acyclovir itself. The mean trough and peak acyclovir concentrations and the daily area under the concentration-time curve acyclovir values at steady state were 2.5 and 8.4 micrograms/ml and 120 h micrograms/ml, respectively, after a dosage of 2,000 mg of valaciclovir four times daily. These values were approximately fivefold greater than those achieved with high dosages of oral acyclovir (800 mg, five times daily) and were not affected by continued use of medications necessary for management of advanced HIV disease. Thus, 2,000 mg of valaciclovir given orally four times daily should be evaluated for its potential efficacy in suppressing cytomegalovirus and other herpes group virus infections not optimally managed with current oral acyclovir therapy.

Acyclovir↗
PubMed1995

Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans.

Valaciclovir (Valtrex), the L-valyl ester of acyclovir, is undergoing clinical development for the treatment and suppression of herpesviral diseases. The absolute bioavailability of acyclovir from valaciclovir and the metabolic disposition of valaciclovir were investigated with healthy volunteers in two separate studies. In a randomized, crossover study, 12 fasting healthy volunteers each received 1,000 mg of oral valaciclovir and a 1-h intravenous infusion of 350 mg of acyclovir. The mean absolute bioavailability of acyclovir was 54.2%, a value three to five times that obtained previously with oral acyclovir. A similar estimate of 51.3% was made from urinary recovery of acyclovir. In the second study, four fasting volunteers received a single oral dose of 1,000 mg of [14C]valaciclovir. The majority of plasma radioactivity was accounted for by acyclovir, with very low plasma valaciclovir concentrations (mean maximum concentration of drug in plasma = 0.19 microM), which were undetectable after 3 h postdose. By 168 h, more than 90% of the administered radioactive dose was recovered, with approximately 45% in urine and 475 in feces. More than 99% of the radioactivity recovered in urine corresponded to acyclovir and its known metabolites, 9-(carboxymethoxymethyl)guanine and 8-hydroxy-9- [(2-hydroxyethoxy)methyl]guanine, with valaciclovir accounting for less than 0.5% of the dose. Acyclovir, but no valaciclovir, was detected in fecal samples. These studies show that after oral administration to humans, valaciclovir is rapidly and virtually completely converted to acyclovir to provide a high level of acyclovir bioavailability in comparison with that following oral administration of acyclovir. The plasma acyclovir exposure obtained following oral administration of valaciclovir is similar to that achieved with doses of intravenous acyclovir, which are effective in the treatment and suppression of the less susceptible herpesviral diseases.

Acyclovir↗
PubMed1995

Comparison of efficacies of famciclovir and valaciclovir against herpes simplex virus type 1 in a murine immunosuppression model.

A mouse model of herpes simplex virus type 1 infection in an immunocompromised host was established by using cyclosporin-A to impair T-cell function. Following inoculation of herpes simplex virus type 1 into the skin of the ear pinna, cyclosporin-A prolonged virus replication in the skin and neural tissues compared with that in immunocompetent mice. This model was used to investigate the activity of famciclovir (FCV) and valaciclovir (VACV), which are oral products of the antiherpesvirus agents penciclovir and acyclovir, respectively. Both prodrugs gave similar blood profiles of the antiherpesvirus agents in normal and cyclosporin-treated mice. The compounds were administered by the oral route at 50 mg/kg per dose twice daily for 5 days. Both compounds were very effective at clearing infectious virus from the tissues despite the immunosuppression; FCV-treated animals cleared virus from the ear pinna more rapidly than VACV-treated animals. The areas under the concentration-time curve (AUC) for virus replication with time were reduced to 50 and 30% of control values for ear pinna and brain stem, respectively, with VACV therapy and to < 5% in both tissues by FCV. When treatment was continued to day 10, the reductions in AUC for ear and brain stem, respectively, were to 33 and 26% of control values with VACV and to < 3 and < 5% with FCV. However, on cessation of the antiviral treatment, there was a reproducible recurrence of infectious virus in the tissues obtained from VACV-treated mice. The recurrence of infectious virus was also evident after 10 days of treatment with VACV. In mice which had received FCV for 10 or 5 days, these was no resumption of virus replication in the ear pinna or brain stem. When dosing was reduced to once per day, both compounds were less effective at controlling the infection. Nevertheless, no recurrence of infectious virus was observed on cessation of FCV therapy.

2-Aminopurine↗
PubMed1995

Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults.

Acyclovir treatment of acute herpes zoster speeds rash healing and decreases pain and ocular complications. The limited oral bioavailability of acyclovir necessitates frequent dosing. Valaciclovir, the l-valyl ester of acyclovir, is rapidly and almost completely converted to acyclovir in vivo and gives three- to fivefold increases in acyclovir bioavailability. In a randomized, double-blind, multicenter study, the safety and efficacy of oral valaciclovir given at a dosage of 1,000 mg three times daily for 7 or 14 days and oral acyclovir given at a dosage of 800 mg five times daily for 7 days were compared in immunocompetent adults aged > or = 50 years with herpes zoster. Patients were evaluated for 6 months. The intent-to-treat analysis (1,141 patients) showed that valaciclovir for 7 or 14 days significantly accelerated the resolution of herpes zoster-associated pain (P = 0.001 and P = 0.03, respectively) compared with acyclovir; median pain durations were 38 and 44 days, respectively, versus 51 days for acyclovir. Treatment with valaciclovir also significantly reduced the duration of postherpetic neuralgia and decreased the proportion of patients with pain persisting for 6 months (19.3 versus 25.7%). However, there were no differences between treatments in pain intensity or quality-of-life measures. Cutaneous manifestations resolved at similar rates in all groups. Adverse events were similar in nature and prevalence among groups, and no clinically important changes occurred in hematology or clinical chemistry parameters. Thus, in the management of immunocompetent patients > or = 50 years of age with localized herpes zoster, valaciclovir given at 1,000 mg three times daily for 7 days accelerates the resolution of pain and offers simpler dosing, while it maintains the favorable safety profile of acyclovir.

Acyclovir↗
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↗
PubMed1995

Pharmacokinetics of new antiherpetic agents.

Valaciclovir and famciclovir, two new prodrugs (for aciclovir and penciclovir, respectively) have similar pharmacokinetics in many regards. Both have good but incomplete bioavailability, with the conversion to the active forms taking place in the liver, but by different cytosolic enzymes. Absorption and conversion are consistent in relevant patient groups, including those with liver disease. The pharmacokinetics of both active molecules are also similar in being mainly renally eliminated, a significant component of which is tubular secretion, and elimination half-lives from plasma of approximately 2.2 to 2.5 hours. Dosage adjustment is required in the presence of renal impairment. No clinically important drug interactions have been identified with either drug. The choice between the two agents is likely to depend on clinical factors such as tolerability, safety, efficacy, compliance and possibly cost, rather than on their pharmacokinetics.

2-Aminopurine↗
PubMed1995

Estimating the value of a generic quality-of-life measure.

In this paper, data from a clinical trial of a new antiviral agent for treating patients with zoster are used to answer the following question: Does the Nottingham Health Profile (NHP) add to the information obtained from the clinical measures? Three ways in which the NHP could add information are measured. First, Cox's regression analysis is used to determine whether health-related quality-of-life scores obtained at diagnosis give information about disease prognosis. Second, changes in mean NHP scores in different dimensions are computed after pain resolution to determine whether NHP scores provide more sensitive indicators of disease resolution. Third, linear regression is used to determine whether the impacts of disease on quality of life are measured adequately by the clinical parameters. These analyses show that use of the physical mobility and energy dimensions of the NHP increases understanding of disease prognosis; demonstrates the continuing impact of zoster on patients' sleep patterns and energy levels, disease symptoms not included as clinical measures, that persist after the cessation of zoster-associated pain; and gives a measure of the impact of zoster on the patient, which includes unmeasured and measured levels of severity.

Acyclovir↗
PubMed1994

Acyclovir--and beyond.

Over the past 15 years, acyclovir has become established as standard therapy for the management of herpes simplex virus infections, but there are areas where improvements might be made. Acyclovir has a relatively low oral bioavailability. As a result, valaciclovir, the L-valine ester of acyclovir, is being developed. This new drug produces enhanced plasma levels of acyclovir following oral dosing, which will not only allow more convenient dosing for the treatment of herpes simplex virus and varicella zoster virus (VZV) infections, but also mean that valaciclovir has the potential for superior clinical efficacy over acyclovir. This may broaden the potential utility of the drug to include human cytomegalovirus prophylaxis. Other new drugs in the antiherpes area include penciclovir and its pro-drug famciclovir, which have antiviral characteristics similar to acyclovir but no clinical benefit over and above that seen with acyclovir has been demonstrated. The synthesis of new specific antiherpes compounds has led to the discovery of a novel nucleoside analogue, 882C87, which has significantly greater activity against VZV than acyclovir. The compound also has a longer plasma half-life than acyclovir which may permit less frequent dosing.

Acyclovir↗
PubMedDate not supplied

Metabolic fate and pharmacokinetics of the acyclovir prodrug valaciclovir in cynomolgus monkeys.

Valaciclovir, the L-valyl ester of acyclovir (ZOVIRAX), demonstrated good oral absorption and nearly complete conversion to acyclovir in cynomolgus monkeys, indicating its suitability as an orally administered prodrug. The major urinary metabolites of [8-14C]valaciclovir, administered orally (10 and 25 mg/kg) or intravenously (10 mg/kg) to male monkeys, were acyclovir (46%-59% of urinary radioactivity), 8-hydroxyacyclovir (25%-30%), and 9-(carboxymethoxymethyl)guanine (CMMG) (11%-12%). Following oral and intravenous dosing, intact prodrug accounted for only 0.5% and 6% of urinary radioactivity, respectively. Dose-independent kinetics were observed for acyclovir derived from orally administered [8-14C]valaciclovir at the 10 and 25 mg/kg dose levels, with both AUC (24 and 60 microM.hr, respectively) and Cmax (8 and 23 microM, respectively) increasing nearly in proportion to the dose. Acyclovir was present in plasma at all sampling times (5 min to 7 hr postdose) after both oral doses, whereas the prodrug was not detected following either oral dose. The elimination of acyclovir after oral administration was monophasic, with an apparent half-life of 1.3-1.5 hr. Similar to acyclovir, both 8-hydroxyacyclovir and CMMG demonstrated dose-independent kinetics with apparent elimination half-lives of 1-1.6 hr. Intravenously administered [8-14C]valaciclovir (10 mg/kg) was rapidly converted to acyclovir, with the elimination half-life of acyclovir (0.9 hr) being 1.5-fold that of the prodrug (0.6 hr). The oral bioavailability of acyclovir derived from valaciclovir in cynomolgus monkey was 67 +/- 13%, representing a significant improvement over the limited bioavailability after acyclovir administration to primates.

Acyclovir↗
PubMedDate not supplied

Metabolic disposition of the acyclovir prodrug valaciclovir in the rat.

The prodrug valaciclovir demonstrated good oral absorption, rapid distribution and elimination, and extensive biotransformation to acyclovir in male CD rats. The mean urinary excretion of radioactivity following oral and intravenous administration of [8-14C]valaciclovir (25 mg/kg) was 65% and 95% of the dose, respectively. Acyclovir was the predominant radiolabeled urinary metabolite accounting for 57% and 65% of the dose, respectively, with valaciclovir accounting for 2% and 23% of the dose, respectively. Radioactivity from an oral dose of [8-14C]valaciclovir (10 mg/kg) was distributed to all 14 tissues examined 20 min postdose. The stomach, small intestine, kidney, liver, lymph nodes, and skin received the highest exposure to radioactivity, and the brain received the lowest exposure. Radioactivity in most tissues cleared by 24 hr postdose, and that in urine and feces accounted for essentially all of the administered dose by 48 hr postdose. Acyclovir derived from valaciclovir (10 and 25 mg/kg) exhibited dose-independent pharmacokinetics. The Cmax and AUC for acyclovir achieved with orally administered valaciclovir were 8- and 4-fold higher, respectively, than those estimated for an equivalent dose of acyclovir. The half-life of acyclovir derived from valaciclovir was approximately 1 hr, whereas that of valaciclovir was approximately 7 min. Valaciclovir was more efficiently metabolized when administered orally, indicating first-pass intestinal and/or hepatic metabolism. Rapid hydrolysis of valaciclovir in rat liver and intestinal homogenates further suggested the significance of presystemic metabolism. These studies indicate that valaciclovir is an efficient acyclovir prodrug particularly suited for oral administration.

Acyclovir↗