Source: Health Products Regulatory Authority (ZA) Revision Year: 2013 Publisher: LITHA PHARMA (PTY) LTD, 106 16th Road, Midrand, 1685, South Africa
A 20.2.8 Antiviral agent(s)
Valaciclovir, an antiviral, is the L-valine ester of acyclovir. Acyclovir is a purine (guanine) nucleoside analogue.
Valaciclovir is rapidly and almost completely converted in man to acyclovir and valine probably by the enzyme valaciclovir hydrolase.
Acyclovir 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), Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human herpes virus 6 (HHV-6). Acyclovir 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 the UL97 gene of CMV. This gene encodes for the viral kinase which facilitates the intracellular anabolism of acyclovir.
The requirement for activation of acyclovir by a virus specific enzyme largely explains its unique selectivity. The phosphorylation process is completed (conversion from mono- to triphosphate) by cellular kinases.
Acyclovir triphosphate competitively inhibits the virus DNA polymerase and incorporation of this nucleoside analogue results in obligate chain termination, halting virus DNA synthesis and thus blocking virus replication.
Extensive monitoring of clinical isolates from patients receiving acyclovir therapy or prophylaxis has revealed that herpes simplex virus and varicella zoster virus with reduced sensitivity to acyclovir is extremely rare in the immunocompetent and is only found infrequently in severely immunocompromised individuals e.g. solid organ or bone marrow transplant recipients, patients receiving chemotherapy for malignant disease and people infected with the human immunodeficiency virus (HIV). 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 acyclovir 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.
After oral administration valaciclovir is well absorbed and rapidly and almost completely converted to acyclovir and valine. This conversion is probably mediated by valaciclovir hydrolase, an enzyme isolated from human liver. Mean peak acyclovir concentrations are 25 µM (5,7 µg/ml) following a single 1000 mg dose of valaciclovir and occur at a median time of 1,75 hours post dose. The bioavailability of acyclovir from 1000 mg valaciclovir is 54% and is not reduced by food. Mean peak acyclovir concentrations are 15-25 µM (3,3-5,7 µg/ml) following single doses of 500-1000 mg valaciclovir, and occur at a median time of 1,50 hours post dose.
Peak plasma concentrations of valaciclovir are only 4% of acyclovir levels, occur at a median time of 45 to 60 minutes post dose, and are below measurable concentrations 3 hours after dosing. The valaciclovir and acyclovir pharmacokinetic profiles are similar after single and repeat dosing. Binding of acyclovir to plasma proteins is very low (15%). The elimination plasma half-life of acyclovir after both single and multiple dosing with valaciclovir is approximately 3 hours. Less than 1% of the administered dose of valaciclovir is recovered in the urine. Valaciclovir is eliminated principally as acyclovir and the known acyclovir metabolite, 9-carboxymethoxymethyl-guanine (CMMG), in the urine.
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