alacyclovir is the L-valyl ester of the antiviral drug acyclovir, first studied in 1983 along with other acyclovir amino acid esters, searching for prodrugs to improve bioavailability and to decrease the toxicity of acyclovir.1 Valacyclovir is chemically stable in aqueous solution and 54% is absorbed after human oral intake, rapidly and extensively converted to acyclovir and amino acid L-valine. Valacyclovir absorption is not altered by administration with food. 1-3 Valacyclovir was initially approved in USA in June 1995 and has indications for herpes simplex virus (HSV-1 and HSV-2) and varicella zoster virus infection. The Valacyclovir antiviral activity reflects its in vivo conversion to acyclovir. Acyclovir, which is a nucleoside analogue, is phosphorylated by virally-encoded thymidine kinase and subsequently by cellular enzymes, yielding acyclovir triphosphate, which competitively inhibits viral DNA polymerase so that viral DNA production is terminated. Valacyclovir has more favorable pharmacokinetics requiring less frequent dosing and achieving higher blood plasma levels than acyclovir. Valacyclovir, at a dose of 250 mg four times daily, generates an area under the concentration-time curve (AUC) of acyclovir orally at a dose of 800 mg five times daily. Valacyclovir, at a dose of 1,000 mg three times daily produces similar acyclovir AUC as intravenous (IV) acyclovir at a dose of 5 mg/kg every eight hours. 4,5 Valacyclovir can generally be regarded as an acceptable alternative to oral acyclovir when this drug is indicated and features a more convenient dosing schedule. Generally, Valacyclovir is well tolerated, similar to the experience with acyclovir. The product prescribing information contained warnings and precautions of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, acute renal failure and central nervous system adverse reactions. 2,3,6 Valacyclovir prescriptions in the USA outnumbered acyclovir at least since 2007 by 27% (3,339,913 vs. 2,627,727 prescriptions) and increased by 26.67% in the 10 years to 2017, while acyclovir prescriptions increased by 43.34% in the same period. 7 Acyclovir nephrotoxicity is explained by crystal nephropathy and acute interstitial nephritis mechanisms, but acute tubular necrosis can also occur. 8,9

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