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Pharmacokinetics of the acyclovir pro-drug valaciclovir after escalating single-and multiple-dose administration to normal volunteers
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1993
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The study examined the pharmacokinetics and safety of valaciclovir, a pro‑drug of acyclovir, in two phase I, placebo‑controlled trials in healthy volunteers. The trials included a single‑dose cohort (100–1000 mg) and a multiple‑dose cohort (250–2000 mg), each enrolling eight valaciclovir recipients and four placebo controls. Valaciclovir was rapidly and extensively converted to acyclovir, yielding 3–5× higher oral bioavailability than high‑dose acyclovir and achieving Cmax and AUC comparable to intravenous acyclovir at the highest doses, with a favorable safety profile that supports further clinical evaluation. Clinical Pharmacology & Therapeutics 1993;54:595–605.
The pharmacokinetics and safety of the L-valyl ester pro-drug of acyclovir, valaciclovir (256U87), were investigated in two phase I, placebo-controlled trials in normal volunteers. These included a single-dose study with doses from 100 to 1000 mg (single cohort) and a multiple-dose investigation with doses from 250 to 2000 mg (five separate cohorts). In each cohort, eight subjects received valaciclovir and four subjects received placebo. Pharmacokinetic findings for valaciclovir and acyclovir were consistent in the two studies. Valaciclovir was rapidly and extensively converted to acyclovir, resulting in significantly greater acyclovir bioavailability (~ threefold to fivefold) compared with that historically observed with high-dose (800 mg) oral acyclovir. At the higher valaciclovir doses, acyclovir maximum concentration and daily area under the concentration-time curve approximated those obtained with intravenous acyclovir. The favorable safety profile and enhanced acyclovir bioavailability from valaciclovir administration has prompted additional clinical evaluations for zoster and herpes simplex virus treatment, as well as cytomegalovirus suppression in immunocompromised patients. Clinical Pharmacology and Therapeutics (1993) 54, 595–605; doi:10.1038/clpt.1993.196