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Pharmacology: Pharmacodynamics: Mechanism of action: Valaciclovir, an antiviral, is the L-valine ester of aciclovir. Aciclovir is a purine (guanine) nucleoside analogue.
Valaciclovir is rapidly and almost completely converted in man to aciclovir and valine, probably by the enzyme referred to as valaciclovir hydrolase.
Aciclovir is a specific inhibitor of the herpes viruses with in vitro activity against herpes simplex viruses (HSV) type 1 and type 2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr Virus (EBV), and human herpes virus 6 (HHV-6). Aciclovir inhibits herpes virus DNA synthesis once it has been phosphorylated to the active triphosphate form.
The first stage of phosphorylation requires the activity of a virus-specific enzyme. In the case of HSV, VZV and EBV this enzyme is the viral thymidine kinase (TK), which is only present in virus infected cells. Selectivity is maintained in CMV with phosphorylation, at least in part, being mediated through the phosphotransferase gene product of UL97. This requirement for activation of aciclovir by a virus specific enzyme largely explains its selectivity.
The phosphorylation process is completed (conversion from mono- to triphosphate) by cellular kinases. Aciclovir triphosphate competitively inhibits the virus DNA polymerase and incorporation of this nucleoside analogue result in obligate chain termination, halting virus DNA synthesis and thus blocking virus replication.
Pharmacodynamic effects: Resistance is normally due to a thymidine kinase deficient phenotype which results in a virus which is profoundly disadvantaged in the natural host. Infrequently, reduced sensitivity to aciclovir has been described as a result of subtle alterations in either the virus thymidine kinase or DNA polymerase. The virulence of these variants resembles that of the wild-type virus.
Extensive monitoring of clinical HSV and VZV isolates from patients receiving aciclovir therapy or prophylaxis has revealed that virus with reduced sensitivity to aciclovir is extremely rare in the immunocompetent and is only found infrequently in severely immunocompromised individuals e.g. organ or bone marrow transplant recipients, patients receiving chemotherapy for malignant disease and people infected with the human immunodeficiency virus (HIV).
Pharmacokinetics: Absorption: In a study of the pharmacokinetics of valaciclovir and aciclovir during late pregnancy, the steady-state daily aciclovir AUC (area under plasma concentration-time curve) following valaciclovir 1000 mg was approximately 2 times greater than that observed with oral aciclovir at 1200 mg daily.
In patients with HIV infection, the disposition and pharmacokinetic characteristics of aciclovir after oral administration of single or multiple doses of 1000 mg or 2000 mg Valtrex are unaltered compared with healthy subjects.
After oral administration valaciclovir is well absorbed and rapidly and almost completely converted to aciclovir and valine. This conversion is probably mediated by an enzyme isolated from human liver referred to as valaciclovir hydrolase.
The bioavailability of aciclovir from 1000 mg valaciclovir is 54%, and is not reduced by food. Valacyclovir pharmacokinetics are not dose-proportional. The rate and extent of absorption decrease with increasing dose, resulting in a less than proportional increase in Cmax over the therapeutic dose range and a reduced bioavailability at doses above 500 mg. Mean peak aciclovir concentrations are 10 to 37 micromoles (2.2 to 8.3 micrograms/mL) following single doses of 250 to 2000 mg valaciclovir to healthy subjects with normal renal function, and occur at a median time of 1 to 2 h post dose.
Peak plasma concentrations of valaciclovir are only 4% of aciclovir levels, occur at a median time of 30 to 100 min post dose, and are at or below the limit of quantification 3 h after dosing. The valaciclovir and aciclovir pharmacokinetic profiles are similar after single and repeat dosing.
Herpes zoster and herpes simplex do not significantly alter the pharmacokinetics of valaciclovir and aciclovir after oral administration of valaciclovir.
Distribution: Binding of valaciclovir to plasma proteins is very low (15%).
Metabolism: After oral administration, Valacyclovir is converted to aciclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Aciclovir is converted to a small extent to the metabolites 9-(carboxymethoxy) methylguanine (CMMG) by alcohol and aldehyde dehydrogenase and to 8-hydroxy-aciclovir (8-OH-ACV) by aldehyde oxidase.
Approximately 88% of the total combined plasma exposure is attributable to aciclovir, 11% to CMMG and 1% to 8-OH-ACV. Neither Valacyclovir nor aciclovir is metabolised by cytochrome P450 enzymes.
Elimination: In patients with end-stage renal disease, the average elimination half-life of aciclovir after valaciclovir administration is approximately 14 hours.
In patients with normal renal function the plasma elimination half-life of aciclovir after both single and multiple dosing with valaciclovir is approximately 3 h. Less than 1% of the administered dose of valaciclovir is recovered in the urine as unchanged drug.
Valaciclovir is eliminated in the urine principally as aciclovir (greater than 80% of the recovered dose) and the known aciclovir metabolite, 9-(carboxymethoxy) methylguanine (CMMG).
Non-clinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Mutagenicity: The results of mutagenicity tests in vitro and in vivo indicate that Valacyclovir is unlikely to pose a genetic risk to humans.
Carcinogenicity: Valacyclovir was not carcinogenic in studies performed in mice and rats.
Teratogenicity: Valacyclovir was not teratogenic in rats and rabbits. Valacyclovir is almost completely metabolised to acyclovir. Experiments with subcutaneous administration of acyclovir did not produce teratogenic effects in rats and rabbits. In additional studies in rats, foetal abnormalities were observed at subcutaneous doses that produced plasma levels of 100 mcg/ml and maternal toxicity.
