Acyclovir is approved for the treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV)infections in children by the intravenous and oral routes. However, its use by the oral route in children younger than 2 years of age is limited due to a lack of pharmacokinetic data. The objectives of the present study were to determine the typical pharmacokinetics of an oral suspension of acyclovir given to children younger than 2 years of age and the interindividual variabilities in the values of the pharmacokinetic parameters in order to support the proposed dosing regimen (24 mg/kg of body weight three times a day for patients younger than 1 month of age or four times a day otherwise). Children younger than age 2 years with HSV or VZV infections were enrolled in a multicenter study. Children were treated for at least 5 days with an acyclovir oral suspension. Plasma samples were obtained at steady state, before acyclovir administration, and at 2, 3, 5, and 8 h after acyclovir administration. Acyclovir concentrations were measured by radioimmunoassay. The data were analyzed by a population approach. Data for 79 children were considered in the pharmacokinetic study (212 samples, 1 to 5 samples per patient). Acyclovir clearance was related to the estimated glomerular filtration rate, body surface area, and serum creatinine level. The volume of distribution was related to body weight. The elimination half-life decreased sharply during the first month after birth, from 10 to 15 h to 2.5 h. Bioavailability was 0.12. The interindividual variability was less pronounced when the parameters were normalized with respect to body weight. Hence, dosage adjustment by body weight is recommended for this population. Simulations showed that the length of time that acyclovir remains above the 50% inhibitory concentration during a 24-h period was more than 12 h for HSV but not for VZV. The proposed dosing regimen seems adequate for the treatment of HSV infections, while for the treatment of VZV infections, a twofold increase in the dose seems necessary for children older than age 3 months.Acyclovir is currently used for the prevention and treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections (7). It is available at different dosages in the form of tablets, oral suspensions (containing 200, 400, or 800 mg in 10 ml), and injectable solutions. About 20 clinical studies have documented the use of acyclovir in children (for a review, see reference 24). Most frequently, acyclovir has been administered intravenously. Hintz et al. (8) recommended 10 mg/kg of body weight every 8 h (q8h) for neonates, while Blum et al.(2) recommended 250 mg/m 2 (for HSV infections) and 500 mg/m 2 (for HSV encephalitis and VZV infections) q8h in children between 3 months and 12 years of age. Owing to the ease of its administration and dosage adjustment, the oral suspension is also used in children. The recommended dosage in neonates is 100 mg four times a day (q.i.d.) (HSV infections) and 200 mg q.i.d. (for VZV infections). I...

Aims  Lamotrigine, an antiepileptic drug, is cleared from the systemic circulation mainly by glucuronidation. The possibility of changes in the pharmacokinetics of lamotrigine in plasma owing to hepatic dysfunction has been evaluated. Methods  Thirty‐six subjects, including 24 patients with various degrees of liver cirrhosis and 12 healthy volunteers received a single 100 mg dose of lamotrgine. Blood samples were taken for 7 days in all subjects, except nine with severe cirrhosis, who had a 29 day blood sampling period. Results  The pharmacokinetics of lamotrigine were comparable between the patients with moderate cirrhosis (corresponding to Child‐Pugh grade A) and the healthy subjects. Plasma oral clearance mean ratios (90% confidence interval) in patients with severe cirrhosis without or with ascites (corresponding, respectively, to Child‐Pugh grade B and C) to healthy subjects were, respectively, 60% (44%, 83%) and 36% (25%, 52%). Plasma half‐life mean ratios (90% confidence interval) in these two patient groups to healthy subjects were, respectively, 204% (149%, 278%) and 287% (202%, 408%). Conclusions  Lamotrigine administered as a single oral dose of 100 mg was well tolerated in all groups. Initial, escalation and maintenance doses should generally be reduced by approximately 50 or 75% in patients with Child‐Pugh Grade B or C cirrhosis. Escalation and maintenance doses should be adjusted according to clinical response.

The effects of probenecid and cimetidine on the pharmacokinetics of valaciclovir and its metabolite acyclovir have been investigated. Twelve healthy male volunteers participated in this open single-dose study with a four-way-crossover randomized and balanced design. At the first of four administrations, volunteers in four groups received 1 g of valaciclovir alone, valaciclovir with 1 g of probenecid, valaciclovir with 800 mg of cimetidine, or valaciclovir with a combination of probenecid and cimetidine. At three subsequent administrations, drug regimens were alternated among groups so that each group received each regimen. Probenecid and cimetidine increased the mean maximum concentrations in serum (C max ) of valaciclovir by 23 and 53% and the areas under the concentration-time curves (AUC) for valaciclovir by 22 and 73%, respectively; probenecid and cimetidine also increased the mean acyclovir C max by 22 and 8% and its AUC by 48 and 27%, respectively. The combination had a greater effect than either drug alone. Their effects may be due to competitive inhibition of membrane transport of valaciclovir and acyclovir in the liver and kidney. Neither cimetidine nor probenecid affected the absorption of valaciclovir. Both probe drugs reduced the rate of valaciclovir metabolism but not its extent. These pharmacokinetic modifications did not affect the tolerability of valaciclovir.Valaciclovir (Valtrex) is the L-valine ester of acyclovir and is extensively converted to the antiherpetic compound acyclovir by hepatic first-pass metabolism following oral administration. Its bioavailability as valaciclovir is three-to fivefold greater than acyclovir's oral bioavailability (13). The active metabolite acyclovir is excreted 85% unchanged in the urine, with the rate of renal clearance (CL R ) being three times that of the glomerular filtration rate, indicating that renal excretion has a significant tubular-secretion component. Valaciclovir and acyclovir, which have anionic and cationic forms in plasma, are secreted by organic anion and cation transporters. Acyclovir CL R is reduced by probenecid (6), which was thought to be due to inhibition of the renal tubular secretion of acyclovir by the anionic pathway.We investigated the effects of probenecid and cimetidine on valaciclovir pharmacokinetics, as these drugs have been reported to inhibit the metabolism of some compounds and the active membrane transport of a number of organic anions and cations (4,6,8,9,12). Additionally, we examined the effects of probenecid and cimetidine on the pharmacokinetics of acyclovir. The drug interactions at the renal level were modeled as a function of the concentrations of the interaction drugs in plasma in order to characterize more precisely their mechanisms and potential consequences. MATERIALS AND METHODS Study design.We employed an open, randomized, balanced, crossover study design with four drug treatments separated by intervals of at least 1 week. Twelve healthy male volunteers (age range, 22 to 43 years; weight range, 54 to 111 kg) par...

Valaciclovir is rapidly and extensively converted to acyclovir. In this study we investigated the potential interaction between oral valaciclovir and Maalox. On each of three occasions 18 healthy volunteers received a single oral dose of 1000 mg valaciclovir, or 30 mL Maalox 65 min after valaciclovir administration, or 30 mL Maalox 30 min before valaciclovir. Acyclovir plasma concentrations and pharmacokinetic parameters were not significantly affected by administration of Maalox before or after valaciclovir. Therefore, there is no need for restriction of valaciclovir dosing in patients receiving antacid medication.