Valaciclovir (BW256U87): The L-valyl ester of acyclovir

Abstract

Valaciclovir (BW256U87) is an L-valyl ester of acyclovir, which is extensively and almost completely converted to acyclovir. In healthy human volunteers, single valaciclovir doses of 100-1000 mg resulted in dose-proportional increases in acyclovir area under the curve (AUC). The 1,000 mg dose produced an acyclovir peak plasma concentration (Cmax) of 5-6 micrograms/ml, AUC6 of 19 hr. micrograms/ml, time to maximum plasma concentration (Tmax) of 1-2 hr, and half-life (T1/2) of 2.8 hr. Plasma valaciclovir peak levels were < 0.3 micrograms/ml, and the prodrug was undetectable after 3 hr. Multiple valaciclovir doses of 250-2,000 mg given four times daily for 10 days resulted in dose-proportional increases in acyclovir Cmax. There were less than proportional increases in the AUCs. No serious or unexpected adverse events or laboratory abnormalities were reported. In volunteers with advanced human immunodeficiency virus (HIV) disease (absolute CD4 lymphocyte count < 150 cells/microliters), acyclovir and valaciclovir pharmacokinetic results were nearly identical to those in healthy volunteers. At the 2 g dose administered four times daily, steady-state acyclovir Cmax = 8.4 micrograms/ml, Tmax = 2.0 hr, AUC6 = 30.5 hr. micrograms/ml, and T1/2 = 3.3 hr. Nausea, vomiting, diarrhoea, and abdominal pain were commonly reported; however, only one adverse event (diarrhoea) was causally linked to valaciclovir exposure. There were no renal or neurologic adverse events. Valaciclovir is well absorbed and is rapidly converted to acyclovir, resulting in three- to fourfold higher acyclovir levels than can be achieved with oral acyclovir, even in patients with advanced HIV disease. The safety profile is generally favourable, with no evidence of nephrotoxicity or neurotoxicity.

Pharmacokinetics of Acyclovir and Its Metabolites in Cerebrospinal Fluid and Systemic Circulation after Administration of High-Dose Valacyclovir in Subjects with Normal and Impaired Renal Function

“…Following oral administration, valacyclovir is rapidly and nearly completely hydrolyzed to acyclovir by first-pass intestinal and hepatic metabolism (13,27). Acyclovir crosses the blood-brain barrier, a desirable quality for the treatment of herpes encephalitis, neonatal herpes simplex virus infections, and, possibly, multiple sclerosis (7, 28).…”

Drug Transporters and Na+/H+Exchange Regulatory Factor PSD-95/Drosophila Discs Large/ZO-1 Proteins

“…Chemical modifications of this type thus permit involvement of PEPT1 in drug uptake processes in the intestine. This approach has been used previously, most notably in the design of the nucleoside analog valacyclovir (Jacobson, 1993). Valacyclovir, a PEPT1 substrate and amino acid ester derivative of the active drug acyclovir, exhibits a 3-to 5-fold increase in bioavailability (Weller et al, 1993).…”

Bioavailability of Two Different Coated-Tablet Formulations of Valacyclovir of Two Different Strengths (500 mg and 1000 mg) in Healthy Mexican Adult Volunteers

“…Other AEs, regarded as unrelated to the study drug, were: nausea (1) and dizziness (1), which occurred during the washout period; cutaneous rash (1); local post-venipuncture ecchymosis (2); papulous lesion (1), common cold (1) and pharyngitis (1).…”

“…Valacyclovir (2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester-L-valine) is a prodrug of acyclovir, a nucleoside analog with antiviral activity [1]. Valacyclovir is rapidly hydrolyzed both in the lumen of the intestine and in the cytoplasm of the enterocyte.…”