Herpevex Mechanism of Action

Pharmacology: Pharmacodynamics: Aciclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against human herpes viruses, including herpes simplex virus (HSV) type I and II and varicella zoster virus (VZV). The inhibitory activity of aciclovir for HSV I, HSV II and VZV is highly selective. The enzyme thymidine kinase (TK) of normal uninfected cells does not use aciclovir effectively as a substrate, hence toxicity of mammalian host cells is low. However, TK encoded by HSV and VZV converts aciclovir to aciclovir monophosphate, a nucleoside, analogue which is further converted to the diphosphate and finally to the triphosphate by cellular enzymes. Aciclovir triphosphate interferes with the viral DNA polymerase and inhibits viral DNS replication with resultant chain termination following its incorporation into the viral DNA.
Prolonged or repeated courses of aciclovir is severely immune-compromised individuals may result in the selective of virus strains with reduced sensitivity, which may not respond to continued aciclovir treatment. Most of the clinical isolates with reduced sensitivity have been relatively deficient in viral TK. However, strains with altered viral TK or DNA polymerase have also been reported. In vitro exposure of HSV isolates to aciclovir can also lead to the emergence of less sensitive strains. The relationship between the in vitro determined sensitivity of HSV isolate and clinical response to aciclovir therapy is not clear.
Pharmacokinetics: The absorption of Aciclovir from the gut is only partial. Following doses of 200 mg, 400 mg and 800 mg, administered four-hourly, the mean steady state peak plasma concentrations (C^ssMax) were 3.1 micromol (0.7 micrograms/ml), 5.3 micromol (1.2 micrograms/ml) and 8 micromol (1.8 micrograms/ml), respectively. Equivalent trough plasma levels (C^ssMin) were 1.8 micromol (0.4 micrograms/ml), 2.7 micromol (0.6 micrograms/ml) and 4 microMol (0.9 micrograms/ml), respectively.
The terminal plasma half life of aciclovir is about 2.9 hours after intravenous administration in adults. Tubular secretion in addition to glomerular filtration contributes to the renal elimination of the drug is indicated by the fact that renal clearance of aciclovir is substantially greater than creatinine clearance. Most of the drug is excreted unchanged. The only significant metabolite of aciclovir, 9 - carboxymethoxymethyl-guanine, accounts for approximately 10-15% of the administered dose recovered from the urine. The terminal half life of aciclovir and the area under the plasma concentration time curve is extended by 18% and 40%, respectively, when it is administered one hour after 1 gram of probenecid.
Following a one hour infusion of 2.5mg/kg, 5mg/kg and 10mg/kg in adults, the mean steady state peak plasma concentrations (C^ssmax) were 22.7 microMol (5.1 micrograms/ml), 43.6 microMol (9.8 micrograms/ml) and 92 microMol (20.7 micrograms/ml), respectively. The corresponding trough levels (C^ssmin), 7 hours later, were 2.2 microMol (0.5 micrograms/ml), 3.1 microMol (0.7 micrograms/ml), and 10.2 microMol (2.3 micrograms/ml), respectively.
When a dose of 250 mg/m2 was substituted for 5 mg/kg and a dose of 500 mg/m2 for 10 mg/kg, in children over 1 year of age, similar mean peak (C^ssmax) and trough (C^ssmin) levels were observed. The C^ssmax was found to be 61.2 microMol (13.8 micrograms/ml) and C^ssmin to be 10.1 microMol (2.3 micrograms/ml) in neonates and young infants (0-3 months of age) treated every 8 hours with doses of 10mg/kg, administered by infusion over a one-hour period. The terminal plasma half life of aciclovir was 3.8 hours in these patients.
In the elderly, although there is little change in the terminal plasma half life, total body clearance falls with increasing age associated with decreases in creatinine clearance.
The mean terminal half life was found to be 19.5 hours in patients with chronic renal failure. During haemodialysis, the mean aciclovir half life was 5.7 hours with plasma aciclovir levels dropping approximately 60%.
Cerebrospinal fluid levels are approximately 50% of corresponding plasma levels. Plasma protein binding is relatively low (9 to 33%) and drug interactions involving binding site displacement are not anticipated.