Source: Υπουργείο Υγείας (CY) Revision Year: 2020 Publisher: Codal-Synto Ltd, 21 Constantinoupoleos Street, 3011 Limassol, Cyprus
Pharmacotherapeutic group: Antivirals for systemic use
ATC code: J05AB01
Aciclovir is a synthetic purine nucleoside analogue with in vitro and in vivo activity against human herpes viruses including herpes simplex (types I and II) and Varicella zoster.
The inhibitory activity of aciclovir is highly selective. Thymidine kinase enzyme in human cells does not use aciclovir as a substrate effectively, thus toxicity for mammalian cells is low. Virally produced thymidine kinase does use aciclovir, converting it to aciclovir monophosphate, which is further converted to diphosphate and then triphosphate by cellular enzymes. Aciclovir triphosphate interferes with viral DNA polymerase and following incorporation in viral DNA inhibits DNA replication and causes chain termination.
Aciclovir is only partially absorbed from the gut. Mean steady state peak plasma concentrations (Cssmax) following doses of 200mg aciclovir administered four-hourly were 3.1 microMol (0.7 microgram/ml) and the equivalent trough plasma levels (Cssmin) were 1.8 microMol (0.4 microgram/ml). Corresponding steady-state plasma concentrations following doses of 400mg and 800mg aciclovir administered four-hourly were 5.3 microMol (1.2 microgram/ml) and 8 microMol (1.8 microgram/ml) respectively, and equivalent trough plasma levels were 2.7 microMol (0.6 microgram/ml) and 4 microMol (0.9 microgram/ml).
In adults the terminal plasma half-life of aciclovir after administrations 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-carboxymethocymethylguanine is the only significant metabolite of aciclovir and accounts for approximately 10-15% of the administered dose recovered from the urine. When aciclovir is administered one hour after the administration of 1g of probenecid the terminal half-life is prolonged by 18% and the area under the curve for plasma concentrations is extended by 40%.
In adults, mean steady state peak plasma concentrations (Cssmax) following a one hour infusion of 2.5mg/kg, 5mg/kg and 10mg/kg were 22.7 microMol (5.1 microgram/ml) 43.6 microMol (9.8 microgram/ml) and 92 microMol (20.7 microgram/ml) respectively. The corresponding trough levels (Css min) 7 hours later were 2.2 microMol (0.5micrograms/ml), 3.1 microMol (0.7 micrograms/ml), and 10.2 microMol (2.3 micrograms/ml) respectively.
In children over 1 year of age similar peak (Cssmax) and trough (Cssmin) levels were observed when a dose of 250mg/m² was substituted for 5mg/kg and a dose of 500mg/m² was substituted for 10mg/kg. In neonates and young infants (0 to 3 months of age) treated with doses of 10mg/kg administered by infusion over a one-hour period every 8 hours the Cssmax was found to be 61.2 microMol (13.8 micrograms/ml) and Cssmin to be 10.1 microMol (2.3micrograms/ml). The terminal plasma half-life in these patients was 3.8 hours. 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.
In patients with chronic renal failure the mean terminal half-life was found to be 19.5 hours. Mean plasma half-life during haemodialysis is 5.7 hours. Plasma aciclovir levels dropped approximately 60% during dialysis.
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.
The results of a wide range of mutagenicity test in vitro and in vivo indicate that aciclovir is unlikely to pose a genetic risk to man. Aciclovir was not found to be carcinogenic in long-term studies in the rat and the mouse. 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 subcutaneous doses tat maternal toxicity was produced. The clinical relevance of these findings is uncertain.
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. There is no experience of the effect of Syntovir i.v. on human fertility. There is no experience of the effect of Syntovir i.v. on human fertility. There is no experience of the effect of Syntovir i.v. on human fertility. Syntovir tablets have been shown to have no definitive effect upon sperm count, morphology or motility in man.
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