Zovirax Mechanism of Action

Pharmacotherapeutic group: Direct acting antivirals, Nucleosides and nucleotides excl. reverse transcriptase inhibitors. ATC code: J05AB01.
Pharmacology: Pharmacodynamics: Mechanism of Action: Aciclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against human herpes viruses, including herpes simplex virus (HSV) types 1 and 2, varicella zoster virus (VZV), Epstein Barr virus (EBV) and cytomegalovirus (CMV). In cell culture, aciclovir has the greatest antiviral activity against HSV-1, followed (in decreasing order of potency) by HSV-2, VZV, EBV and CMV.
The inhibitory activity of aciclovir for HSV-1, HSV-2, VZV, EBV and CMV is highly selective. The enzyme thymidine kinase (TK) of normal, non-infected cells does not use aciclovir effectively as a substrate, hence toxicity to mammalian host cells is low; however, TK encoded by HSV, VZV and EBV 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 DNA replication with resultant chain termination following its incorporation into the viral DNA.
Pharmacodynamic Effects: Prolonged or repeated courses of aciclovir in severely immune-compromised individuals may result in the selection 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 isolates and clinical response to aciclovir therapy is not clear.
All patients should be cautioned to ensure they avoid the potential of virus transmission, particularly when active lesions are present.
Clinical Studies: Oral susp/Powd for inj: There is no information on the effect of ZOVIRAX oral formulations & infusion on human female fertility. In a study of 20 male patients with normal sperm count, oral aciclovir administered at doses of up to 1 g per day for up to six months has been shown to have no clinically significant effect on sperm count, motility or morphology.
Pharmacokinetics: Absorption: Dispersible tab: Aciclovir is only partially absorbed from the gut. Mean steady state peak plasma concentrations (C_ssmax) following doses of 200 mg administered four-hourly were 3.1 micromolar (0.7 micrograms/mL) and equivalent trough plasma levels (C_ssmin) were 1.8 micromolar (0.4 micrograms/mL). Corresponding C_ssmax levels following doses of 400 mg and 800 mg administered four-hourly were 5.3 micromolar (1.2 micrograms/mL) and 8 micromolar (1.8 micrograms/mL) respectively, and equivalent C_ssmin levels were 2.7 micromolar (0.6 micrograms/mL) and 4 micromolar (0.9 micrograms/mL).
In adults, mean steady state peak plasma concentrations (C_ssmax) following a one-hour infusion of 2.5 mg/kg, 5 mg/kg and 10 mg/kg and 15 mg/kg were 22.7 micromolar (5.1 micrograms/mL), 43.6 micromolar (9.8 micrograms/mL), 92 micromolar (20.7 micrograms/mL) and 105 micromolar (23.6 micrograms/mL) respectively. The corresponding through levels (C_ssmin) 7 hours later were 2.2 micromolar (0.5 micrograms/mL), 3.1 miromolar (0.7 micrograms/mL), 10.2 micromolar (2.3 micrograms/mL) and 8.8 micromolar (2.0 micrograms/mL), respectively. In children over 1 year of age similar mean peak (C_ssmax) and through (C_ssmin) levels were observed when a dose of 250 mg/m² was substituted for 5 mg/kg and a dose of 500 mg/m² was substituted for 10 mg/kg. In neonates (0 to 3 months of age) treated with doses of 10 mg/kg administered by infusion over a one-hour period every 8 hours the C_ssmax was found to be 61.2 micromolar (13.8 micrograms/mL) and the C_ssmin to be 10.1 micromolar (2.3 micrograms/mL). A separate group of neonates treated with 15 mg/kg every 8 hours showed approximate dose proportional increases, with a C_max of 83.5 micromolar (18.8 micrograms/mL) and C_min of 14.1 micromolar (3.2 micrograms/mL).
Oral susp: Aciclovir is only partially absorbed from the gut. The average oral bioavailability varies between 10 and 20%. Under fasting conditions, mean peak concentrations (C_max) of 0.4 microgram/ml are achieved at approximately 1.6 hours after a 200 mg dose administered as oral suspension or capsule. Mean peak plasma concentrations (C_ssmax) increase to 0.7 microgram/ml (3.1 micromoles) at steady state following doses of 200 mg administered every four hours. A less than proportional increase is observed for C_ssmax levels following doses of 400 mg and 800 mg administered four-hourly, with values reaching 1.2 and 1.8 microgram/ml (5.3 and 8 micromoles), respectively.
Powd for inj: Not Applicable.
Distribution: The mean volume of distribution of 26 L indicates that aciclovir is distributed within total body water. Apparent values after oral administration (Vd/F) ranged from 2.3 to 17.8 L/kg. As plasma protein binding is relatively low (9 to 33%), drug interactions involving binding site displacement are not anticipated. Cerebrospinal fluid levels are approximately 50% of corresponding plasma levels at steady-state.
Metabolism: Aciclovir is predominantly excreted unchanged by the kidney. The only known urinary metabolite is 9-[(carboxymethoxy)methyl] guanine, and accounts for 10-15% of the dose excreted in the urine.
Elimination: In neonates (0 to 3 months of age) treated with doses of 10 mg/kg administered by infusion over a one-hour period every 8 hours the terminal plasma half-life was 3.8 hours.
Dispersible tab: In adults the terminal plasma half life of aciclovir after administration of intravenous aciclovir is about 2.9 hours. Most of the drug is excreted unchanged by the kidney. Renal clearance of aciclovir is substantially greater than creatinine clearance, indicating that tubular secretion in addition to glomerular filtration contributes to the renal elimination of the drug. 9-carboxymethoxy-methylguanine is the only significant metabolite of aciclovir and accounts for approximately 10 to 15% of the dose excreted in the urine. When aciclovir is given one hour after 1 gram of probenecid the terminal half life and the area under the plasma concentration time curve is extended by 18% and 40% respectively.
Oral susp/Powd for inj: Mean systemic exposure (AUC_0-∞) to aciclovir ranges between 1.9 and 2.2 microgram*h/mL after a 200 mg dose. In adults the terminal plasma half-life after oral administration has been shown to vary between 2.8 and 4.1 hours. Renal clearance of aciclovir (CLr=14.3 L/h) is substantially greater than creatinine clearance, indicating that tubular secretion, in addition to glomerular filtration, contributes to the renal elimination of the drug. The half-life and total clearance of aciclovir are dependent on renal function. Therefore, dosage adjustment is recommended for renally impaired patients.
Special Patient Populations: In patients with chronic renal failure the mean terminal half-life was found to be 19.5 hours. The mean aciclovir half-life during haemodialysis was 5.7 hours. Plasma aciclovir levels dropped approximately 60% during dialysis.
In the elderly total body clearance falls with increasing age, associated with decreases in creatinine clearance, although there is little change in the terminal plasma half-life.
Dispersible tab/Oral susp: Studies have shown no apparent changes in the pharmacokinetic behaviour of aciclovir or zidovudine when both are administered simultaneously to HIV infected patients.
Toxicology: Non-Clinical Information/Preclinical Safety Data: The results of a wide range of mutagenicity tests in vitro and in vivo indicate that aciclovir is unlikely to pose a genetic risk to man.
Aciclovir was not carcinogenic in long-term studies in the rat and the mouse.
Largely reversible adverse effects on spermatogenesis in association with overall toxicity in rats and dogs have been reported only at doses of aciclovir greatly in excess of those employed therapeutically. Two-generation studies in mice did not reveal any effect of orally administered aciclovir on fertility.
Systemic administration of aciclovir in intentionally accepted standard tests did not produce embryotoxic or teratogenic effects in rabbits, rats or mice. In a non-standard test in rats, foetal abnormalities were observed but only following such high subcutaneous doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain.