Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans

Abstract

Valaciclovir (Valtrex), the L-valyl ester of acyclovir, is undergoing clinical development for the treatment and suppression of herpesviral diseases. The absolute bioavailability of acyclovir from valaciclovir and the metabolic disposition of valaciclovir were investigated with healthy volunteers in two separate studies. In a randomized, crossover study, 12 fasting healthy volunteers each received 1,000 mg of oral valaciclovir and a 1-h intravenous infusion of 350 mg of acyclovir. The mean absolute bioavailability of acyclovir was 54.2%, a value three to five times that obtained previously with oral acyclovir. A similar estimate of 51.3% was made from urinary recovery of acyclovir. In the second study, four fasting volunteers received a single oral dose of 1,000 mg of [ 14 C]valaciclovir. The majority of plasma radioactivity was accounted for by acyclovir, with very low plasma valaciclovir concentrations (mean maximum concentration of drug in plasma ‫؍‬ 0.19 M), which were undetectable after 3 h postdose. By 168 h, more than 90% of the administered radioactive dose was recovered, with approximately 46% in urine and 47% in feces. More than 99% of the radioactivity recovered in urine corresponded to acyclovir and its known metabolites, 9-(carboxymethoxymethyl)guanine and 8-hydroxy-9-[(2-hydroxyethoxy)methyl]guanine, with valaciclovir accounting for less than 0.5% of the dose. Acyclovir, but no valaciclovir, was detected in fecal samples. These studies show that after oral administration to humans, valaciclovir is rapidly and virtually completely converted to acyclovir to provide a high level of acyclovir bioavailability in comparison with that following oral administration of acyclovir. The plasma acyclovir exposure obtained following oral administration of valaciclovir is similar to that achieved with doses of intravenous acyclovir, which are effective in the treatment and suppression of the less susceptible herpesviral diseases.

Valacyclovir for the prevention of cytomegalovirus infection after allogeneic stem cell transplantation: a single institution retrospective cohort analysis

“…Serum levels and area under the curve (AUC) are comparable to those achieved with intravenous acyclovir. [13][14][15] Recent prospective randomized studies using valacyclovir for the prophylactic treatment of CMV infection have shown safety and efficacy in patients with renal transplants and AIDS. [16][17][18][19] However, the benefit of this approach for CMV prophylaxis in SCT recipients has not been reported.…”

Valacyclovir as a Therapeutic Agent in Acute Retinal Necrosis: Two Case Reports

“…Valacyclovir and famciclovir have superior plasma bioavailability to acyclovir as oral preparations [11]. The aim of the present study is to add to this evidence with 2 additional cases of ARN treated with valacyclovir .…”

“…The 2 g t.i.d. dose was well tolerated and neither patient developed systemic adverse effects associated with the treatment.treatment of varicella zoster acute retinal necrosis syndrome, with good anatomic and functional results [10].Valacyclovir and famciclovir have superior plasma bioavailability to acyclovir as oral preparations [11]. The aim of the present study is to add to this evidence with 2 additional cases of ARN treated with valacyclovir .…”

Apical Sodium Dependent Bile Acid Transporter (ASBT, SLC10A2): A Potential Prodrug Target

“…Acyclovir valylchenodeoxycholate was designed to assess potential for hASBT targeting as against PepT1 targeting. Valacyclovir (L-valine ester prodrug of acyclovir) is an prodrug of acyclovir that has improved the oral bioavailability of acyclovir with human oral bioavailability of 54% 14,63 . Valacyclovir is a substrate for the PepT1 intestinal transporter, with a Ki=4.08 mM in PepT1 expressing Xenopus laevis oocytes 64 and Ki=1.10 mM in stable lines of CHO/PepT1 13 .…”