Pharmacotherapeutic Group: Antiviral agent.
Pharmacology: Pharmacodynamics: Mechanism of Action: Acyclovir 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, acyclovir 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 acyclovir 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 acyclovir effectively as a substrate, hence toxicity to mammalian host cells is low; however, TK encoded by HSV, VZV and EBV converts acyclovir to acyclovir monophosphate, a nucleoside analogue, which is further converted to the diphosphate and finally to the triphosphate by cellular enzymes. Acyclovir 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 acyclovir in severely immuno-compromised individuals may result in the selection of virus strains with reduced sensitivity, which may not respond to continued acyclovir treatment.
Most of the clinical isolates with reduced sensitivity have been relatively deficient in viral TK however, strains with altered viral TK or viral DNA polymerase have also been reported. In vitro exposure of HSV isolates to acyclovir 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 acyclovir therapy is not clear.
All patients should be cautioned to ensure they avoid the potential of virus transmission, particularly when active lesions are present.
Pharmacokinetics: Absorption: In adults, mean steady-state peak plasma concentration (Cssmax) levels following a 1-hour infusion of 2.5 mg/kg, 5 mg/kg and 10 mg/kg and 15 mg/kg were 22.7 micromolar (mcM) (5.1 mcg/mL), 43.6 mcM (9.8 mcg/mL), 92 mcM (20.7 mcg/mL) and 105 mcM (23.6 mcg/mL), respectively. The corresponding trough plasma levels (Cssmin) levels 7 hours later were 2.2 mcM (0.5 mcg/mL), 3.1 mcM (0.7 mcg/mL), 10.2 mcM (2.3 mcg/mL) and 8.8 mcM (2 mcg/mL), respectively. In children >1 year, similar mean Cssmax and Cssmin 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 (0-3 months) treated with doses of 10 mg/kg administered by infusion over a 1-hr period every 8 hours, the Cssmax was found to be 61.2 mcM (13.8 mcg/mL) and the Cssmin to be 10.1 mcM (2.3 mcg/mL). A separate group of neonates treated with 15 mg/kg every 8 hours showed approximate dose proportional increases, with a Cmax of 83.5 mcM (18.8 mcg/mL) and Cmin of 14.1 mcM (3.2 mcg/mL).
Tablet: Acyclovir is only partially absorbed from the gut. Mean Cssmax following doses of 200 mg administered 4 hrly were 3.1 mcM (0.7 mcg/mL) and equivalent Cssmin were 1.8 mcM (0.4 mcg/mL). Corresponding Cssmax levels following doses of 400 mg and 800 mg administered 4 hrly were 5.3 mcM (1.2 mcg/mL) and 8 mcM (1.8 mcg/mL), respectively, and equivalent Cssmin levels were 2.7 mcM (0.6 mcg/mL) and 4 mcM (0.9 mcg/mL).
Distribution: Cerebrospinal fluid levels are approximately 50% of corresponding plasma levels. Plasma protein-binding is relatively low (9-33%) and drug interactions involving binding site displacement are not anticipated.
Elimination: In adults, the terminal plasma half-life of acyclovir after administration of IV acyclovir is about 2.9 hours. Most of the drug is excreted unchanged by the kidney. Renal clearance of acyclovir 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 acyclovir and accounts for approximately 10-15% of the dose excreted in the urine. When acyclovir is given 1 hour after 1 g of probenecid, the terminal half-life and the area under plasma concentration-time curve (AUC) is extended by 18% and 40%, respectively.
In neonates (0-3 months) treated with doses of 10 mg/kg administered by infusion over a 1-hour period every 8 hours, the terminal plasma half-life was 3.8 hours.
Special Patient Populations: In patients with chronic renal failure, the mean terminal half-life was found to be 19.5 hours. The mean acyclovir half-life during hemodialysis was 5.7 hours. Plasma acyclovir 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.
Tablet: Studies have shown no apparent changes in the pharmacokinetic behaviour of acyclovir or zidovudine when both are administered simultaneously to HIV infected patients.
Clinical Studies: There is no information on the effect of Zovirax IV for infusion on human female fertility. In a study of 20 male patients with normal sperm count, oral acyclovir administered at doses of up to 1 g/day for up to 6 months has been shown to have no clinically significant effect on sperm count, motility or morphology.
Toxicology: Preclinical Safety Data: The results of a wide range of mutagenicity tests in vitro and in vivo indicate that acyclovir does not pose a genetic risk to man.
Acyclovir 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 acyclovir greatly in excess of those employed therapeutically. Two (2)-generation studies in mice did not reveal any effect of orally administered acyclovir on fertility.
Systemic administration of acyclovir in internationally accepted standard tests did not produce embryotoxic or teratogenic effects in rabbits, rats or mice. In a nonstandard test in rats, fetal abnormalities were observed but only following such high subcutaneous doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain.