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 cytomegaloviruses (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, noninfected cells does not use aciclovir effectively as 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 immunocompromised 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 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: There is no information on the effect of Zovirax oral formulations 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/day for up to 6 months has been shown to have no clinically significant effect on sperm count, motility or morphology.
Pharmacokinetics: Absorption: Aciclovir is only partially absorbed from the gut. Mean steady state peak plasma concentrations (Cssmax) following doses of 200 mg administered 4 hrly were 3.1 micromoles (0.7 mcg/mL) and the equivalent trough plasma levels (Cssmin) were 1.8 micromoles (0.4 mcg/mL). Corresponding Cssmax levels following doses of 400 mg and 800 mg administered 4-hrly were 5.3 micromoles (1.2 mcg/mL) and 8 micromoles (1.8 mcg/mL) respectively, and equivalent Cssmin levels were 2.7 micromoles (0.6 mcg/mL) and 4 micromoles (0.9 mcg/mL).
In adults, mean steady state peak plasma concentrations (Cssmax) following a 1-hr infusion of 2.5 mg/kg, 5 mg/kg, 10 mg/kg and 15 mg/kg were 22.7 micromoles (5.1 mcg/mL), 43.6 micromoles (9.8 mcg/mL), 92 micromoles (20.7 mcg/mL) and 105 micromoles (23.6 mcg/mL), respectively. The corresponding trough levels (Cssmin) 7 hrs later were 2.2 micromoles (0.5 mcg/mL), 3.1 micromoles (0.7 mcg/mL), 10.2 micromoles (2.3 mcg/mL) and 8.8 micromoles (2 mcg/mL), respectively. In children >1 year similar mean peak (Cssmax) and trough (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.
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 is not anticipated.
Elimination: In adults the terminal plasma half-life (t½) of aciclovir after administration of IV aciclovir is about 2.9 hrs. 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 10-15% of the dose excreted in the urine. When aciclovir is given 1 hr after 1 g of probenecid the terminal t½ and the area under the plasma concentration time curve is extended by 18% and 40%, respectively.
Special Patient Populations: In patients with chronic renal failure the mean terminal t½ was found to be 19.5 hrs. The mean aciclovir t½ during haemodialysis was 5.7 hrs. 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 t½.
Toxicology: 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 internationally 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 SC doses that maternal toxicity was produced. The clinical relevance of these findings is uncertain.