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.

These results indicate that impaired renal function will have little effect on the plasma concentrations of lamotrigine achieved for a given dosing regimen.

Aiiirs T h e aim of this study was to compare the pharmacokinetics of the antiepileptic agent, lamotrigine, in patients with chronic renal failure and healthy volunteers. Methods Non-compartmental pharmacohnetics of a single oral dose (200 nig) of the anti-epileptic agent, lamotrigine, and its main metabolite, lamotrigine N'glucuronide, were determined for 10 patients with chronic renal failure of mean estimated creatinine clearance 18 ml ininand a control group of 11 healthy volunteers, matched for age and gender. ResultsFor lamotrigine, there were no significant differences in Cmas, frnZ, AUC, t+,z, C L / F and amount excreted in urine although ttz tended to be longer for the renal failure group with a mean (fs.d.) of 35.9f 10.7 h us 2 7 . 8 k 4 . 3 h for the control group. For the renal failure group, Vz/F was 18% higher (95% C1 1% to 39%) compared with controls and CL, was reduced to 61% (95% C1 46% to 80%) of the control group value. For lamotrigine glucuronide, C,m,, was increased 4-fold (95% C1 3.1 to 5.3) and A U C 7.8-fold (95% C1 6.0 to 10.1) in the renal failure group compared with controls. CL, was approximately %fold lower and apparent tt was increased by 53% (95% C1 27% to 84%). Concentrations of an N2-methylated cardo-active metabolite, previously observed in dogs, were below the limit of detection (2 ng r n -l ) of the ASTED/h.p.l.c. assay in the renal failure group as well as controls. Conc-hsiorzs These results indicate that impaired renal function will have little effect on the plasma concentrations of lamotrigine achieved for a given dosing regimen.

Aims Changes in both digoxin and aciclovir renal clearance following coadministration with some other renally eliminated drugs have been reported. The potential interaction of valaciclovir, with its antiherpetic metabolite aciclovir, and digoxin was investigated. Methods Twelve healthy volunteers (seven males, five females) participated in an open, randomized, four-period crossover study. Valaciclovir, 1000 mg, was given alone on one occasion, and on another, after the second of two 0.75 mg digoxin doses administered 12 h apart. Blood samples and all urine were collected up to 12 h following the valaciclovir dose for aciclovir radioimmunoassay. On a third occasion, digoxin was given alone and on a fourth, with 1000 mg valaciclovir three times/day for 8 days starting 12 h before the first digoxin dose. Blood samples were taken up to 168 h and all urine collected up to 24 h following the second dose for digoxin radioimmunoassay. Results There were no clinically significant differences in digoxin or aciclovir pharmacokinetic parameters when digoxin or valaciclovir was given alone or in combination.Conclusions No dosage adjustment is required when valaciclovir and digoxin are coadministered.

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