PHARMACOKINETICS OF THE ACYCLOVIR PRO-DRUG VALACICLOVIR AFTER ESCALATING SINGLE-DOSE AND MULTIPLE-DOSE ADMINISTRATION TO NORMAL VOLUNTEERS

The pharmacokinetics and safety of the L-valyl ester pro-drug of acycl ovir, 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-do se investigation with doses from 250 to 2000 mg (five separate cohorts ). In each cohort, eight subjects received valaciclovir and four subje cts received placebo. Pharmacokinetic findings for valaciclovir and ac yclovir were consistent in the two studies. Valaciclovir was rapidly a nd extensively converted to acyclovir, resulting in significantly grea ter acyclovir bioavailability (approximately threefold to fivefold) co mpared with that historically observed with high-dose (800 mg) oral ac yclovir. At the higher valaciclovir doses, acyclovir maximum concentra tion and daily area under the concentration-time curve approximated th ose obtained with intravenous acyclovir. The favorable safety profile and enhanced acyclovir bioavailability from valaciclovir administratio n has prompted additional clinical evaluations for zoster and herpes s implex virus treatment, as well as cytomegalovirus suppression in immu nocompromised patients.