Brands, Medical Use, Clinical Data
Drug Category
Dosage Forms
Brands / Synonyms
Acyclovir; Valaciclovir; Valaciclovir Hcl; Valaciclovir Hydrochloride; Valacyclover Hydrochloric; Valacyclover Hydrochloride; Valacyclovir Hydrochloride; Valtrex; Zovirax
Indications
For the treatment or suppression of cold sores (herpes labialis), herpes zoster (shingles), genital herpes in immunocompetent individuals, and recurrent genital herpes in HIV-infected individuals.
Pharmacology
Valacyclovir is a prodrug and synthetic purine nucleoside analogue with inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV). Valacyclovir is almost completely converted to acyclovir and L-valine. The inhibitory activity of valacyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, which is then converted into acyclovir diphosphate and triphosphate by cellular enzymes. Acyclovir is selectively converted to the active triphosphate form by cells infected with herpes viruses.
Mechanism of Action
Valacyclovir is phosphorylated by viral thymidine kinase to acyclovir triphosphate (the active metabolite) which then inhibits herpes viral DNA replication by competitive inhibition of viral DNA polymerase, and by incorporation into and termination of the growing viral DNA chain. When used as a substrate for viral DNA polymerase, acyclovir triphosphate competitively inhibits dATP leading to the formation of 'faulty' DNA. This is where acyclovir triphosphate is incorporated into the DNA strand replacing many of the adenosine bases. This results in the prevention of DNA synthesis, as phosphodiester bridges can longer to be built, destabilizing the strand.
Absorption
After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract. The absolute bioavailability of acyclovir after administration of valacyclovir is 54.5% ± 9.1%.
Toxicity
Adverse effects of overexposure might include headache and nausea.
Biotrnasformation / Drug Metabolism
Valacyclovir is rapidly and almost entirely (~99%) converted to the active compound, acyclovir, and L-valine by first-pass intestinal and hepatic metabolism by enzymatic hydrolysis. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes.
Contraindications
VALTREX is contraindicated in patients with a known hypersensitivity or intolerance to valacyclovir, acyclovir, or
any component of the formulation.
Drug Interactions
The pharmacokinetics of digoxin was not affected by coadministration of Valacyclovir 1 gram 3 times daily, and the pharmacokinetics of acyclovir after a single dose of Valacyclovir (1 gram) was unchanged by coadministration of digoxin (2 doses of 0.75 mg), single doses of antacids (Al3+ or Mg++), or multiple doses of thiazide diuretics. Acyclovir Cmax and AUC following a single dose of Valacyclovir (1 gram) increased by 8% and 32%, respectively, after a single dose of cimetidine (800 mg), or by 22% and 49%, respectively, after probenecid (1 gram), or by 30% and 78%, respectively, after a combination of cimetidine and probenecid, primarily due to a reduction in renal clearance of acyclovir. These effects are not considered to be of clinical significance in subjects with normal renal function. Therefore, no dosage adjustment is recommended when Valacyclovir is coadministered with digoxin, antacids, thiazide diuretics, cimetidine, or probenecid in subjects with normal renal function.
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