Source: Υπουργείο Υγείας (CY) Revision Year: 2014 Publisher: MEDOCHEMIE LTD, 1-10 Constantinoupoleos street, 3011 Limassol, Cyprus
Pharmacotherapeutic group: Nucleosides and nucleotides excl. reverse transcriptase inhibitors, Antivirals for Systemic Use
ATC code: J05AB01
Aciclovir is a synthetic purine nucleoside analogue which has in vitro and in vivo activity against human herpes virus, including Herpes simplex (type I and II) and Varicella zoster.
The inhibitory action 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.
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 viral 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 the HSV isolates and clinical response to aciclovir therapy is not clear.
Aciclovir is only partially absorbed from the gut. Mean steady state peak plasma concentration (Cssmax) following doses of 200 mg administered four-hourly were 3.1 micromol (0.7 micrograms/ml) and equivalent trough plasma levels (Cssmin) were 1.8 micromol (0.4 micrograms/ml). Corresponding Cssmax levels following doses of 400 mg and 800 mg administered four-hourly were 5.3 micromol (1.2 micrograms/ml) and 8 micromol (1.8 micrograms/ml) respectively and equivalent Cssmin levels were 2.7 micromol (0.6 micrograms/ml) and 4 microMol (0.9 micrograms/ml).
In adults the terminal plasma half life 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-carboxymethoxymethyl-guanine is the only significant metabolite of aciclovir and accounts for approximately 10-15% of the administered dose recovered from 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.
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 micrograms/ml), 43.6 microMol (9.8 micrograms/ml) and 92 microMol (20.7 micrograms/ml), respectively. The corresponding trough levels (Cssmin) 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.
In children over 1 year of age 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 5 mg/kg and a dose of 500 mg/m² was substituted for 10 mg/kg. In neonates and young infants (0-3 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 (2.3 micrograms/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 changes in the terminal plasma half life.
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.
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 is 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 that 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 Medovir i.v. or cream on human fertility. Medovir tablets have been shown to have no definitive effect upon sperm count, morphology or motility in man.
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