Valtrex (Valacyclovir)

Classification:
Antiinfective Agents

• Antivirals

Description: Valacyclovir is the L-valyl ester of acyclovir; the result of an effort to develop a prodrug to improve acyclovir oral bioavailability. Improved bioavailability means less frequent dosing for valacyclovir than acyclovir, which is especially beneficial during maintenance therapy. The FDA originally approved valacyclovir for the treatment of herpes zoster (shingles) in immunocompetent patients in June 1995. Valacyclovir has since received additional FDA approvals, including: for treatment of recurrent herpes genitalis in December 1995; for treatment of initial episodes of herpes genitalis in October 1996; for maintenance (i.e., suppressive) therapy of herpes genitalis in otherwise healthy patients in September 1997; for treatment of herpes labialis in September 2002; for the suppression of recurrent genital herpes in HIV-infected individuals in April 2003; and for the reduction of genital herpes transmission in August 2003. Valacyclovir is under investigation for the treatment of CMV prophylaxis in patients with HIV infection or patients receiving organ or bone marrow transplants and has also been studied for the treatment of chickenpox (varicella).

Mechanism of Action: Valacyclovir is rapidly converted to acyclovir, which inhibits DNA synthesis. Acyclovir must be phosphorylated intracellularly to be active. Acyclovir is converted to the monophosphate by viral thymidine kinase, then to diphosphate by cellular guanylate kinase, and finally to the triphosphate by various cellular enzymes. Acyclovir triphosphate competitively inhibits viral DNA polymerase, and to a lesser extent human DNA polymerase. Acyclovir triphosphate also competes with the natural substrate, deoxyguanosine triphosphate, for incorporation into viral DNA. Once incorporated, acyclovir triphosphate inhibits DNA synthesis by acting as a chain terminator. Formation of a complex at the end of the DNA strand may lead to irreversible inactivation of viral DNA polymerase. Herpes virus DNA polymerases differ in sensitivity to acyclovir. Uninfected cells show only minimal phosphorylation of acyclovir, and there is only a small amount of acyclovir taken up into these cells. The concentration of acyclovir triphosphate is 40- to 100- times higher in HSV-infected cells than non-infected cells. Acyclovir is effective only against actively replicating viruses; it does not eliminate the latent herpes virus genome. The range of in vitro minimum inhibitory concentrations of acyclovir are as follows: herpes simplex-1, 0.02 - 0.9 mcg/ml; herpes simplex-2, 0.3 - 2.2 mcg/ml; varicella-zoster virus, 0.8 - 4 mcg/ml; cytomegalovirus 2 - 57 mcg/ml; and Epstein-Barr virus, 1.6 mcg/ml.

Viral resistance to acyclovir may occur due to loss of thymidine kinase activity, alterations in thymidine kinase substrate specificity, or decreased DNA-polymerase sensitivity. The alterations in these enzymes occur due to point mutations or base insertions or deletions in the specific genes. The most common mechanism of resistance is loss of thymidine kinase activity. These viral variants are also cross resistant to other antiviral agents activated by thymidine kinase (e.g., ganciclovir or penciclovir). Thymidine kinase negative variants of herpes virus may cause severe disease in infants and immunocompromised patients. Acyclovir-resistant herpes simplex virus has been seen in immunocompromised patients, patients with concurrent HIV infection, and immunocompetent patients with genital herpes. Repeated systemic treatment may lead to the development of viral resistance in immunosuppressed patients.

Valtrex Caplets(Tab 500 mg)

Pharmacokinetics: Valacyclovir is administered orally and is rapidly absorbed. Absorption is unaffected by administration with food. In healthy volunteers, relative bioavailability of valacyclovir compared to that of acyclovir was 3.3 to 5 times greater; acyclovir bioavailability is 54% when administered as valacyclovir compared to 15 - 30% when administered as acyclovir itself. It has been suggested valacyclovir may saturate absorption sites along the GI tract. Although repeat dosing does not reduce acyclovir concentrations, the Cmax and AUC for acyclovir are not dose-proportional. Valacyclovir in doses of 1 - 2 g PO four times daily yields plasma acyclovir concentrations and AUC levels similar to that obtained after IV administration of acyclovir 5 - 10 mg/kg every 8 hours. As a result of improved oral bioavailability, valacyclovir requires less frequent dosing than acyclovir. Valacyclovir binds to plasma protein in the range 13.5 - 17.9%. Valacyclovir is converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Acyclovir undergoes some metabolism by aldehyde oxidase, alcohol dehydrogenase, and aldehyde dehydrogenase to produce inactive metabolites. Microsomal hepatic enzymes do not contribute to the metabolism of valacyclovir or acyclovir. Plasma concentrations of valacyclovir are low and transient and become undetectable after 3 hours. Peak valacyclovir plasma levels are generally < 0.5 mcg/ml at all dosage levels. Acyclovir is eliminated primarily by the kidneys. Plasma elimination half-life of acyclovir is between 2.5 and 3.3 hours in patients with normal renal function.