Pharmacokinetics of Oral Acyclovir in Neonates and in Infants: a Population Analysis

Abstract

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...

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