Single-dose pharmacokinetics of famciclovir in infants and population pharmacokinetic analysis in infants and children

Abstract

A multicenter, open-label study evaluated the single-dose pharmacokinetics and safety of a pediatric oral famciclovir (prodrug of penciclovir) formulation in infants aged 1 to 12 months with suspicion or evidence of herpes simplex virus infection. Individualized single doses of famciclovir based on the infant's body weight ranged from 25 to 175 mg. Eighteen infants were enrolled (1 to <3 months old [n = 8], 3 to <6 months old [n = 5], and 6 to 12 months old [n = 5]). Seventeen infants were included in the pharmacokinetic analysis; one infant experienced immediate emesis and was excluded. Mean C(max) and AUC(0-6) values of penciclovir in infants <6 months of age were approximately 3- to 4-fold lower than those in the 6- to 12-month age group. Specifically, mean AUC(0-6) was 2.2 microg h/ml in infants aged 1 to <3 months, 3.2 microg h/ml in infants aged 3 to <6 months, and 8.8 microg h/ml in infants aged 6 to 12 months. These data suggested that the dose administered to infants <6 months was less than optimal. Eight (44.4%) infants experienced at least one adverse event with gastrointestinal events reported most commonly. An updated pharmacokinetic analysis was conducted, which incorporated the data in infants from the present study and previously published data on children 1 to 12 years of age. An eight-step dosing regimen was derived that targeted exposure in infants and children 6 months to 12 years of age to match the penciclovir AUC seen in adults after a 500-mg dose of famciclovir.

Trial registration: ClinicalTrials.gov NCT00448227.

FIG. 1.

Mean (± the standard deviation) plasma concentration-time profiles of penciclovir and 6-deoxypenciclovir after a single oral famciclovir dose administered to infants stratified by age. Group 1, ages 1 to <3 months; group 2, ages 3 to < 6 months, group 3, ages 6 to 12 months. Symbols: ▪, penciclovir; ○, 6-deoxypenciclovir.

FIG. 2.

Relationship between AUC_0-6 of penciclovir and body weight (BW) or age. Infant 0511_0001 received an incorrect dose, i.e., 175 mg instead of 200 mg. (Upper) Observed AUC_0-6 versus BW after single oral famciclovir dose. (Lower) Observed AUC_0-6 versus age after single oral famciclovir dose. Group 1 (♦), ages 1 to <3 months; group 2 (□), ages 3 to <6 months; group 3 (▴), 6 to 12 months.

FIG. 3.

Relationship between penciclovir oral clearance (CL/F) and body weight (BW) for 67 infants and children aged 1 month to 12 years old. Individual values represent the model-based CL/F values. Modeled CL/F represents the equation 2 [CL/F = 23.3·(BW/20)^0.75]. Power (individual values) shows the fit of an empirical power model to the individual data: CL/F = 2.3873·BW^0.7658.

FIG. 4.

Relationship between model-based penciclovir oral clearance normalized to a body weight (BW) of 70 kg (CL/F/70 kg BW) for 67 infants and children aged 1 month to 12 years old. The curve is a local regression model (LOESS).

FIG. 5.

Model-based estimates of AUC of penciclovir versus body weight in pediatric patients (n = 55) between 6 months and 12 years given a single dose of famciclovir according to the proposed eight-step dosing table. The squares represent the model-based individual values. The middle, lower and upper horizontal lines represent the mean (8.94 μg·h/ml), minimum (6.31 μg·h/ml), and maximum AUC (11.84 μg·h/ml), respectively, in adults (n = 24) after a single 500-mg dose (19).

FIG. 6.

Simulated typical penciclovir concentration-time profiles after a single theoretical dose to match adult exposure (AUC = 8.94 μg·h/ml) in infants and children 1 month to 12 years of age.