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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) 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 deoxyribonucleic acid (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 result in obligate chain termination, halting virus deoxyribonucleic acid (DNA) synthesis and thus blocking virus replication.
Pharmacodynamic Effects: Resistance is normally due to a thymidine kinase-deficient phenotype which results in a virus that 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 the 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, 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. Valaciclovir pharmacokinetics are not dose-proportional. The rate and extent of absorption decrease with increasing dose, resulting in a less than proportional increase in peak plasma concentration (Cmax) over the therapeutic dose range and a reduced bioavailability at doses >500 mg. 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, occurring 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.
Distribution: Binding of valaciclovir to plasma proteins is very low (15%). Cerebrospinal fluid (CSF) penetration, determined by CSF/plasma area under the concentration-time curve (AUC) ratio, is about 25% for aciclovir and the metabolite 8-hydroxy-aciclovir (8-OH-ACV), and about 2.5% for the metabolite 9-(carboxymethoxy)methylguanine (CMMG) (see Special Patient Populations as follows).
Metabolism: After oral administration, valaciclovir 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-CMMG by alcohol and aldehyde dehydrogenase and to 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 valaciclovir nor aciclovir is metabolized by cytochrome P-450 enzymes.
Elimination: In patients with normal renal function, the plasma elimination t½ of aciclovir after both single and multiple dosing with valaciclovir is approximately 3 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-CMMG.
Special Patient Populations: Renal Impairment: The elimination of aciclovir is correlated to renal function and exposure to aciclovir will increase with increased renal impairment. In patients with end-stage renal disease, the average elimination t½ of aciclovir after Valtrex administration is approximately 14 hrs, compared with about 3 hrs for normal renal function (see Dosage & Administration).
Exposure to aciclovir and its metabolites CMMG and 8-OH-ACV in plasma and CSF was evaluated at steady state after multiple-dose valaciclovir administration in 6 subjects with normal renal function [mean creatinine clearance (CrCl) of 111 mL/min, range: 91-144 mL/min] receiving 2000 mg every 6 hrs and 3 subjects with severe renal impairment (mean CrCl of 26 mL/min, range: 17-31 mL/min) receiving 1500 mg every 12 hrs.
In plasma, as well as CSF, concentrations of aciclovir, CMMG and 8-OH-ACV were on average 2, 4 and 5-6 times higher, respectively, in severe renal impairment compared with normal renal function. There was no difference in the extent of CSF penetration (as determined by CSF/plasma AUC ratio) for aciclovir, CMMG and 8-OH-ACV between the 2 populations (see Distribution as previously mentioned).
Hepatic Impairment: Pharmacokinetic data indicate that hepatic impairment decreases the rate of conversion of valaciclovir to aciclovir but not the extent of conversion. Aciclovir t½ is not affected.
Pregnant Women: In a study of the pharmacokinetics of valaciclovir and aciclovir during late pregnancy, the steady state daily aciclovir AUC following valaciclovir 1000 mg daily was approximately 2 times greater than that observed with oral aciclovir at 1200 mg daily.
See Use in lactation under Precautions for information on transfer into breast milk.
HIV Infection: In patients with HIV infection, the disposition and pharmacokinetic characteristics of aciclovir after oral administration of single or multiple doses of valaciclovir 1000 mg or 2000 mg are unaltered compared with healthy subjects.
Organ Transplantation: 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.
Toxicology: Preclinical Safety Data: The results of mutagenicity tests in vitro and in vivo indicate that valaciclovir is unlikely to pose a genetic risk to humans.
Valaciclovir was not carcinogenic in bioassays performed in mice and rats.
Valaciclovir did not affect fertility in male or female rats dosed by the oral route.
At high parenteral doses of aciclovir testicular atrophy and aspermatogenesis have been observed in rats and dogs.
Valaciclovir was not teratogenic in rats or rabbits. It is almost completely metabolized to aciclovir. Subcutaneous (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.
