ACYCLOVIR — acyclovir tablet
Each 800-mg tablet of acyclovir contains 800mg of acyclovir and the inactive ingredients FD&C Blue No. 2, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate.
Each 400-mg tablet of acyclovir contains 400mg of acyclovir and the inactive ingredients magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate.
Acyclovir is a white, crystalline powder with the molecular formula C8H11N5O3 and a molecular weight of 225. The maximum solubility in water at 37°C is 2.5mg/mL. The pka’s of acyclovir are 2.27 and 9.25.
The chemical name of acyclovir is 2-amino -1, 9 -dihydro -9 — [(2-hydroxyethoxy) methyl]-6 H -purin-6 -one; it has the following structural formula:
The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir mono phosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In vitro, acyclovir triphosphate stops replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation into 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 in vitro 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 (IC50 ), vary greatly depending upon a number of factors. Using plaque-reduction assays, the IC50 against herpes simplex virus isolates ranges from 0.02 to 13.5mcg/mL for HSV-1 and from 0.01 to 9.9mcg/mL for HSV-2. The IC50 for acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12 to 10.8mcg/mL. Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC50 of 1.35mcg/mL.
Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of HSV and VZV with reduced susceptibility to acyclovir have been recovered from immunocompromised patients, especially with advanced HIV infection. While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have been isolated. TK-negative mutants may cause severe disease in infants and immunocompromised adults. The possibility of viral resistance to acyclovir should be considered in patients who show poor clinical response during therapy.
The pharmacokinetics of acyclovir after oral administration have been evaluated in healthy volunteers and in immunocompromised patients with herpes simplex or varicella-zoster virus infection. Acyclovir pharmacokinetic parameters are summarized in Table 1.
|Plasma protein binding||9 % to 33%|
|Plasma elimination half-life||2.5 to 3.3 hr|
|Average oral bio availability||10 % to 20 %*|
|* Bio availability decreases with increasing dose.|
In one multiple-dose, crossover study in healthy subjects (n = 23), it was shown that increases in plasma acyclovir concentrations were less than dose proportional with increasing dose, as shown in Table 2. The decrease in bioavailability is a function of the dose and not the dosage form.
Table 2. Acyclovir Peak and Trough Concentrations at Steady State
|Parameter||200 mg||400 mg||800 mg|
|SS C max||0.83 mcg /mL||1.21 mcg /mL||1.61 mcg /mL|
|SS C trough||0.46 mcg /mL||0.63 mcg /mL||0.83 mcg /mL|
The only known urinary metabolite is 9 -[(carboxymethoxy)methyl]guanine.
Adults with Impaired Renal Function:
The half-life and total body clearance of acyclovir are dependent on renal function. A dosage adjustment is recommended for patients with reduced renal function (see DOSAGE AND ADMINISTRATION)
Acyclovir plasma concentrations are higher in geriatric patients compared with younger adults, in part due to age-related changes in renal function. Dosage reduction may be required in geriatric patients with underlying renal impairment (see PRECAUTIONS: Geriatric Use).
In general, the pharmacokinetics of acyclovir in pediatric patients is similar to that of adults. Mean half-life after oral doses of 300mg/m2 and 600mg/m2 in pediatric patients aged 7 months to 7 years was 2.6 hours (range 1.59 to 3.74 hours).
Coadministration of probenecid with intravenous acyclovir has been shown to increase the mean acyclovir half-life and the area under the concentration-time curve. Urinary excretion and renal clearance were correspondingly reduced.
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