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 (HSV) types I and II and varicella zoster virus (VZV).

The inhibitory activity of aciclovir for HSV I, HSV II and VZV is highly selective. The enzyme thymidine kinase (TK) of normal, uninfected cells does not use aciclovir effectively as a substrate, hence toxicity of mammalian host cells is low; however, TK encoded by HSV and VZV 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.

Prolonged or repeated courses of aciclovir in severely immune-compromised 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 HSV isolates and clinical response to aciclovir therapy is not clear.

Pharmacokinetic Properties

5.2.     Pharmacokinetic Properties
Zovirax Tablets 200mg, Zovirax Tablets 400mg:
Acyclovir is incompletely absorbed from the GI tract. Approximately 20% is absorbed shortly after administration. When the dose is increased to 600 mg or more, acyclovir is absorbed relatively less well.
The maximum steady-state plasma concentration (Css max) after a 200-mg dose given at four- hour intervals was 3 micromol/L, and the lowest concentration (Css min) was 1.6 micromol/L.
Corresponding concentrations after a 800-mg dose were 6.9 and 3.5 micromol/L, respectively. Most of it is excreted unchanged via the kidneys.
When a group of neonates were treated with acyclovir 15 mg/kg every eight hours, an approximate dose-dependent increase was observed, with a Cmax of 83.5 micromol/L (18.8 micrograms/mL) and a Cmin of 14.1 micromol/L (3.2 micrograms/mL).

As renal excretion of acyclovir exceeds creatinine clearance, elimination is likely to occur by both glomerular filtration and tubular secretion. Acyclovir has a plasma half-life of approximately three hours in patients with normal renal function. Acyclovir's only significant metabolite is 9-carboxymethoxymethylguanine, which makes up 10–15% of the excreted drug in the urine. In chronic renal failure, the mean terminal half-life of the drug is on average 19.5 hours. The mean concentration of acyclovir decreases by approximately 60% during dialysis.

In the elderly, total clearance decreases with age, associated with a decrease in creatinine clearance. However, the terminal half-life does not change much. Administration of acyclovir and zidovudine to HIV patients did not cause any measurable changes in the pharmacokinetics of any of the substances. No mutagenicity was observed in the studies on nine of eleven microbial or mammalian cells. An effect was observed in two studies on mammalian cells, but in this case the concentrations were at least x times higher than the plasma concentrations in humans (x depends on the route of administration: 25-fold after i.v.
and 150-fold after oral administration).


Zovirax Tablets Dispersible 800 mg:
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 concentration 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 concentration are approximately 50% of corresponding plasma concentration 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.
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.

There are no pharmacokinetic data for the oral formulation in neonates. The only available pharmacokinetic data are for the IV formulation in this age group


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 concentration dropped approximately 60% during dialysis.