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 (approximately 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.
Smallpox, eradicated in the late 1970s, is considered a serious worldwide threat because of its potential use as a biological weapon. Attempts to develop an antiviral drug for the prophylaxis and treatment of the disease are complicated by the need to demonstrate effective antiviral activity and propose human dosing paradigms based on data generated in animals infected with related orthopoxviruses. This perspective article reviews the difficulties associated with developing an antiviral agent using animal models and the ‘animal efficacy rule’: a FDA regulation designed for situations where human clinical trials are not an option.
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