Pharmacology: Pharmacodynamics Properties: 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) types 1 and 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 1st 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 results 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 eg, organ or bone marrow transplant recipients, patients receiving chemotherapy for malignant disease and people infected with the human immunodeficiency virus (HIV).
Pharmacokinetics: Absorption: 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 valaciclovir 1000 mg is 54%, and is not reduced by food. Mean peak aciclovir concentrations are 10-37 micromoles (2.2-8.3 mcg/mL) following single doses of valaciclovir 250-2000 mg to healthy subjects with normal renal function, and occur at a median time of 1-2 hrs post-dose.
Peak plasma concentrations of valaciclovir are only 4% of aciclovir levels, occur at a median time of 30-100 min post-dose, and are at or below the limit of quantification 3 hrs 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.
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 1200 mg daily.
In patients with HIV infection, the disposition and pharmacokinetic characteristics of aciclovir after oral administration of single or multiple doses of valaciclovir 1000 or 2000 mg are unaltered compared with healthy subjects.
In transplant recipients receiving valaciclovir 2000 mg 4 times daily, aciclovir peak concentrations are similar to or greater than those in healthy volunteers receiving the same dose. The estimated daily AUCs are appreciably greater.
Distribution: Binding of valaciclovir to plasma protein is very low (15%).
Elimination: In patients with normal renal function, the plasma elimination t1/2 of aciclovir after both single and multiple dosing with valaciclovir is approximately 3 hrs. In patients with end-stage renal disease, the average elimination t1/2 of aciclovir after valaciclovir administration is approximately 14 hrs. 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 (>80% of the recovered dose) and the known aciclovir metabolite, 9-(carboxymethoxy) methylguanine (CMMG).
Toxicology: Preclinical Safety Data: The results of mutagenicity tests in vitro and in vivo indicate that Valtrex is unlikely to pose a genetic risk to humans.
Valaciclovir was not carcinogenic in bioassays performed in mice and rats. It did not affect fertility in male or female rats dosed by the oral route.
Valaciclovir was not teratogenic in rats or rabbits. Valaciclovir is almost completely metabolized to aciclovir. SC administration of aciclovir in internationally accepted tests did not produce teratogenic effects in rats or rabbits. In additional studies in rats, fetal abnormalities were observed at SC doses that produced plasma levels of 100 mcg/mL and maternal toxicity.