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.

AimsTo examine the population pharmacokinetics of lamotrigine in patients newly diagnosed with epilepsy and receiving oral lamotrigine monotherapy for up to 48 weeks. Methods The population consisted of 158 Caucasians and 5 Asians of whom 81 were males and 82 females. Age and weight ranged between 14 and 76 years and 41-107 kg, respectively. A one-compartment compartment model with first-order absorption and elimination was fitted to plasma lamotrigine concentration-time profiles from retrospective drug monitoring, using non-linear mixed effect modelling (NONMEM), with first-order estimation. Oral clearance (CL o ), apparent volume of distribution ( V /F) and absorption rate constant (K a ) were the main pharmacokinetic parameters. Results CL o was not significantly influenced by body weight, age, gender, oral contraceptives and dose. However, due to auto-induction CL o increased by 17.3% during the 48 weeks of therapy, from 1.94 to 2.28 l h −1 , and was 28.7% lower inAsians than Caucasian. The final magnitude in interpatient variability was 32%. The effect of the covariates weight, age, race and gender on V /F was examined and none was statistically significant. The final population estimate of V /F was 77.4 l with an interpatient variability of 34%.Conclusions In view of the wide therapeutic margin of lamotrigine and the 21% residual variability in plasma concentrations, the modest significant effects of race and auto-induction on clearance are unlikely to be clinically significant and, thus, no dosage adjustment is warranted for these effects.

Renal glucose excretion increases in a proportional manner with increasing blood glucose. When decreasing blood glucose to euglycaemic blood glucose levels, glucosuria persists so that the classical concept of a renal threshold for glucose excretion cannot be upheld in subjects with type 2 diabetes.

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