Pharmacokinetics and safety of famciclovir in children with herpes simplex or varicella-zoster virus infection

Abstract

Two multicenter, open-label, single-arm, two-phase studies evaluated single-dose pharmacokinetics and single- and multiple-dose safety of a pediatric oral famciclovir formulation (prodrug of penciclovir) in children aged 1 to 12 years with suspicion or evidence of herpes simplex virus (HSV) or varicella-zoster virus (VZV) infection. Pooled pharmacokinetic data were generated after single doses in 51 participants (approximately 12.5 mg/kg of body weight [BW] for children weighing < 40 kg and 500 mg for children weighing > or = 40 kg). The average systemic exposure to penciclovir was similar (6- to 12-year-olds) or slightly lower (1- to < 6-year-olds) than that in adults receiving a 500-mg dose of famciclovir (historical data). The apparent clearance of penciclovir increased with BW in a nonlinear manner, proportional to BW(0.696). An eight-step weight-based dosing regimen was developed to optimize exposure in smaller children and was used in the 7-day multiple-dose safety phases of both studies, which enrolled 100 patients with confirmed/suspected viral infections. Twenty-six of 47 (55.3%) HSV-infected patients who received famciclovir twice a day and 24 of 53 (45.3%) VZV-infected patients who received famciclovir three times a day experienced at least one adverse event. Most adverse events were gastrointestinal in nature. Exploratory analysis following 7-day famciclovir dosing regimen showed resolution of symptoms in most children with active HSV (19/21 [90.5%]) or VZV disease (49/53 [92.5%]). Famciclovir formulation (sprinkle capsules in OraSweet) was acceptable to participants/caregivers. In summary, we present a weight-adjusted dosing schedule for children that achieves systemic exposures similar to those for adults given the 500-mg dose.

Trial registration: ClinicalTrials.gov NCT00098046 NCT00098059.

Figures

FIG. 1.

Plasma drug concentration-time profiles of penciclovir and 6-deoxypenciclovir after a single oral famciclovir dose administered to children stratified by age. Values are means ± standard deviations (error bars). Symbols: ▪, penciclovir; ○, 6-deoxypenciclovir.

FIG. 2.

Relationship between AUC0-∞ of penciclovir and body weight. (Upper) Observed AUC0-∞ (AUC0-inf.) after a single oral famciclovir dose. Participant 0513-00004 received an incorrect dose (i.e., 125 mg instead of the scheduled dose of 225 mg). (Lower) AUC0-∞ predicted for the optimized doses according to the dosing scheme used in the second phase of both studies. Symbols: ⧫, cohort 1 (1 to <2 year olds); □, cohort 2 (2 to <6 year olds); ▴, cohort 3 (6 to ≤12 year olds).

FIG. 3.

Relationship between CL/F of penciclovir and body weight. The line shows the fit of an empirical power model (CL/F = A × BWB) to the data; the equation of the fitted model is given.