Sign Out
Pharmacology: Pharmacodynamics: Mechanism of Action: Aciclovir is a synthetic purine nucleoside analog with a highly selective antiviral activity, dependent upon intracellular activation of the drug to aciclovir triphosphate. Aciclovir is converted to aciclovir monophosphate principally via virus-coded thymidine kinase (TK). The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes (e.g., phosphoglycerate kinase, pyruvate kinase, phosphoenolpyruvate carboxykinase).
Aciclovir also is apparently converted to aciclovir triphosphate by other mechanisms since the drug has some activity against some viruses that do not code for viral TK (e.g., Epstein-Barr virus and cytomegalovirus). Aciclovir triphosphate is formed in virally infected cells in amounts of 40 to 100 times greater than in normal uninfected cells. Aciclovir triphosphate functions as a substrate for and preferential inhibitor of herpesvirus DNA polymerases to a much greater extent than cellular DNA polymerase and thus inhibits viral DNA replication much more effectively than cellular DNA replication. Aciclovir triphosphate is incorporated into the growing viral DNA primer template, inactivates the polymerase, and terminates biosynthesis of the DNA chain.
Antimicrobial Spectrum of Activity: After intracellular conversion of aciclovir to a pharmacologically active triphosphate metabolite, aciclovir is active in vitro against various Herpesviridae including: Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2); Varicella-zoster virus (VSV); Epstein-Barr virus; Herpesvirus simiae (B virus); Cytomegalovirus (CMV).
Aciclovir is much less active against CMV than against many other Herpesviridae, This may occur because CMV does not produce TK and therefore is less able than other viruses to phosphorylate aciclovir to its triphosphate derivative.
Aciclovir is inactive against vaccinia virus, adenovirus type 5, and several RNA viruses.
Pharmacokinetics: Absorption of aciclovir from the gastrointestinal tract is variable and incomplete. Aciclovir is only partially absorbed from the gastrointestinal (GI) tract. It is estimated that 10% to 30% of an oral dose of the drug is absorbed. Some data suggest that GI absorption of aciclovir may be saturable; in a crossover study in which oral aciclovir was administered to healthy adults as 200 mg capsules, 400 mg tablets, or 800 mg tablets 6 times daily, the extent of absorption decreased with increasing dose, resulting in bioavailabilities of 20, 15, or 10%, respectively. In addition, steady-state peak and trough plasma aciclovir levels were not dose proportional over the oral dosage range of 200 to 800 mg 6 times daily, averaging 0.83 and 0.46, 1.21 and 0.63, or 1.61 and 0.83 μg/mL for the 200-, 400-, or 800-mg dosing regimens, respectively.
After oral administration, the peak plasma concentrations of aciclovir usually occur within 1.5 to 2.5 hours.
The mean steady-state peak and trough plasma concentrations of aciclovir in immunocompromised patients were 0.49-0.56 and 0.29-0.31 μg/mL, respectively, after oral administration of aciclovir 200 mg every 4 hours, 1.2 and 0.62 μg/mL, respectively, after oral administration of aciclovir 400 mg every 4 hours, and 2.8 and 1.8 μg/mL, respectively, after oral administration of aciclovir 800 mg (as capsules) every 4 hours.
Food does not appear to affect aciclovir absorption.
Aciclovir is widely distributed into body tissues and fluids including the brain, kidney, saliva, lung, liver, muscle, spleen, uterus, vaginal mucosa and secretions, CSF, and herpetic vesicular fluid. The drug is also distributed into semen, achieving concentrations about 1.4 and 4 times those in plasma during chronic oral therapy at dosages of 400 mg and 1 g daily, respectively.
The apparent volume of distribution of aciclovir is 32.4-61.8 L/1.73 m2 in adults and 28.8, 31.6, 42, or 51.2-53.6 L/1.73 m2 in neonates up to 3 months of age, children 1 to 2 years, 2 to 7 years or 7 to 12 years of age, respectively.
About 9% to 33% of aciclovir is bound to plasma proteins in vitro at plasma concentrations of 0.41 to 5.2 μg/mL. Drug interactions involving binding site displacement is not anticipated.
Aciclovir crosses the placenta. Limited data indicate that the drug is distributed into milk, generally in concentrations greater than concurrent maternal plasma concentrations, possibly via an active transport mechanism.
Aciclovir is metabolized partially to 9-carboxymethoxymethylguanine (CMMG) and minimally to 8-hydroxy-9-(2-hydroxyethoxymethyl)guanine.
Plasma concentrations of aciclovir appear to decline in a biphasic manner. In adults with normal renal function, the mean terminal plasma half life is 2.1 to 3.5 hours.
In patients with chronic renal impairment the mean terminal half life was 19.5 hours. The mean aciclovir half-life during hemodialysis was 5.4 to 5.7 hours, Plasma aciclovir levels dropped at about 60% during dialysis.
In neonates, the half life of aciclovir depends principally on the maturity of renal mechanisms for excretion as determined by gestational age, chronologic age, and weight. In children older than 1 year of age, half life of the drug appears to be similar to that of adults. The mean terminal half life was 3.8 to 4.1,1.9, 2.2 to 2.8, or 3.6 hours in neonates up to 3 months of age, children 1 to 2 years, 2 to 12 years, or 12 to 17 years of age, respectively.
Aciclovir undergoes urinary excretion via glomerular filtration and tubular secretion.
Total body clearance of aciclovir is reported to be 327, 248, 190, or 29 mL/minute per 1.73 m2 in patients with creatinine clearances of greater than 80, 50 to 80, 15 to 50, or 0 mL/minute per 1.73 m2, respectively.
Aciclovir is removed by hemodialysis.
