Valaciclovir

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 virusspecific 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 to aciclovir is normally due to a thymidine kinase deficient phenotype which results in a virus which is disadvantaged in the natural host. 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.

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 host and is 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).

Absorption

Valaciclovir is a prodrug of aciclovir. The bioavailability of aciclovir from valaciclovir is about 3.3 to 5.5-fold greater than that historically observed for oral aciclovir. 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. Valaciclovir pharmacokinetics is not dose-proportional. The rate and extent of absorption decreases with increasing dose, resulting in a less than proportional increase in C_max over the therapeutic dose range and a reduced bioavailability at doses above 500 mg. Aciclovir pharmacokinetic (PK) parameter estimates following single doses of 250 to 2000 mg valaciclovir to healthy subjects with normal renal function are shown below.

C_max = peak concentration; T_max = time to peak concentration; AUC = area under the concentrationtime curve. Values for C_max and AUC denote mean ± standard deviation. Values for T_max denote median and range.

Peak plasma concentrations of unchanged valaciclovir are only about 4% of peak 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, herpes simplex and HIV infection do not significantly alter the pharmacokinetics of valaciclovir and aciclovir after oral administration of valaciclovir compared with healthy adults. 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 proteins is very low (15%). CSF penetration, determined by CSF/plasma AUC ratio, is independent of renal function and was about 25% for aciclovir and the metabolite 8-OH-ACV, and about 2.5% for the metabolite CMMG.

Biotransformation

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(carboxy-methoxy)-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 valaciclovir nor aciclovir is metabolized by cytochrome P450 enzymes.

Elimination

Valaciclovir is eliminated in the urine principally as aciclovir (greater than 80% of the recovered dose) and the aciclovir metabolite CMMG (about 14% of the recovered dose). The metabolite 8-OH-ACV is detected only in small amounts in urine (<2% of the recovered dose). Less than 1% of the administered dose of valaciclovir is recovered in the urine as unchanged drug. In patients with normal renal function the plasma elimination half-life of aciclovir after both single and multiple dosing with valaciclovir is approximately 3h.

Special 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 half-life of aciclovir after valaciclovir administration is approximately 14 hours, compared with about 3 hours for normal renal function.

Exposure to aciclovir and its metabolites CMMG and 8-OH-ACV in plasma and cerebrospinal fluid (CSF) was evaluated at steady-state after multiple-dose valaciclovir administration in 6 subjects with normal renal function (mean creatinine clearance 111 mL/min, range 91-144 mL/min) receiving 2000 mg every 6 hours and 3 subjects with severe renal impairment (mean CLcr 26 mL/min, range 17-31 mL/min) receiving 1500 mg every 12 hours. 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, at severe renal impairment compared with normal renal function.

Hepatic impairment

Pharmacokinetic data indicate that hepatic impairment decreases the rate of conversion of valaciclovir to aciclovir but not the extent of conversion. Aciclovir half-life is not affected.

Pregnant women

A study of the pharmacokinetics of valaciclovir and aciclovir during late pregnancy indicates that pregnancy does not affect the pharmacokinetics of valaciclovir.

Transfer into breast milk

Following oral administration of a 500 mg dose of valaciclovir, peak aciclovir concentrations (C_max) in breast milk ranged from 0.5 to 2.3 times the corresponding maternal aciclovir serum concentrations. The median aciclovir concentration in breast milk was 2.24 micrograms/ml (9.95 micromoles/L). With a maternal valaciclovir dosage of 500 mg twice daily, this level would expose a nursing infant to a daily oral aciclovir dosage of about 0.61 mg/kg/day. The elimination half-life of aciclovir from breast milk was similar to that for serum. Unchanged valaciclovir was not detected in maternal serum, breast milk, or infant urine.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.

Valaciclovir 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 metabolised to aciclovir. Subcutaneous administration of aciclovir in internationally accepted tests did not produce teratogenic effects in rats or rabbits. In additional studies in rats, foetal abnormalities and maternal toxicity were observed at subcutaneous doses that produced plasma aciclovir levels of 100 micrograms/mL (>10-fold higher than 2000 mg single dose valaciclovir in humans with normal renal function).