Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Direct acting antivirals, Nucleosides and nucleotides excl.
reverse transcriptase inhibitors
ATC code: J05AB01.

Aciclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against human herpes viruses, including Herpes simplex virus types 1 and 2 and 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 and EBV is highly selective. The enzyme thymidine kinase (TK) of normal, uninfected 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.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Aciclovir is only partially absorbed from the gut. The average oral bioavailability varies between 10 and 20%. Under fasting conditions, mean peak concentrations (Cmax) 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 (Cssmax) 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 Cssmax concentrations 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.


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 concentrations are approximately 50% of corresponding plasma concentrations at steady-state.


Metabolism
Aciclovir is predominantly excreted unchanged by the kidney. The only significant urinary metabolite is 9-[(carboxymethoxy) methyl]guanine, and accounts for 10-15% of the dose excreted in the urine.


Elimination
In adults mean systemic exposure (AUC0-∞) to aciclovir ranges between 1.9 and 2.2 microgram*h/mL after a 200 mg dose. At this dose, the mean terminal plasma half-life after oral administration has been shown to vary between 2.8 and 4.1 hours.
In adults, the terminal plasma half-life of aciclovir after administration of Zovirax I.V.
is about 2.9 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.
In adults, mean steady state peak plasma concentrations (Cssmax) following a one-hour infusion of 2.5 mg/kg, 5 mg/kg and 10 mg/kg were 22.7 micromolar (5.1 microgram/ml), 43.6 micromolar (9.8 microgram/ml) and 92 micromolar (20.7 microgram/ml) respectively. The corresponding trough concentrations (Cssmin) 7 hours later were 2.2 micromolar (0.5 microgram/ml), 3.1 micromolar (0.7 microgram/ml) and 10.2 micromolar (2.3 microgram/ml) respectively. In children over 1 year of age similar mean peak (Cssmax) and trough (Cssmin) concentrations 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 Cssmax was found to be 61.2 micromolar (13.8 microgram/ml) and the Cssmin to be 10.1 micromolar (2.3 microgram/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 micromolar (18.8 microgram/ml) and Cmin of 14.1 micromolar (3.2 microgram/ml). The terminal plasma half-life in these patients was 3.8 hours.



Special Patient Populations
Elderly
In the elderly patients with normal renal function total clearance falls with increasing age due to decreases in creatinine clearance. However, the possibility of renal impairment in the elderly must be considered and the dosage should be adjusted accordingly.
Renal impairment
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 concentrations dropped approximately 60% during dialysis.


Weight
In a clinical study in which morbidly obese female patients (n=7) were dosed with intravenous aciclovir based on their actual body weight, plasma concentrations were found to be approximately twice that of normal weight patients (n=5), consistent with the difference in body weight between the two groups.