Population pharmacokinetics of intravenous acyclovir in preterm and term infants

Abstract

Background: Acyclovir is used to treat herpes infections in preterm and term infants; however, the influence of maturation on drug disposition and dosing requirements is poorly characterized in this population.

Methods: We administered intravenous acyclovir to preterm and term infants <31 days postnatal age and collected plasma samples. We performed a population pharmacokinetic analysis. The primary pharmacodynamic target was acyclovir concentration ≥3 mg/L for ≥50% of the dosing interval. The final model was simulated using infant data from a clinical database.

Results: The analysis included 28 infants (median 30 weeks gestation). Acyclovir pharmacokinetics was described by a 1-compartment model: clearance (L/h/kg) = 0.305 × [postmenstrual age (PMA)/31.3 weeks]. This equation predicts a 4.5-fold increase in clearance from 25 to 41 weeks PMA. With proposed dosing, the pharmacodynamic target was achieved in 91% of infants: 20 mg/kg every 12 hours in infants <30 weeks PMA; 20 mg/kg every 8 hours in infants 30 to <36 weeks PMA and 20 mg/kg every 6 hours in infants 36-41 weeks PMA.

Conclusions: Acyclovir clearance increased with infant maturation. A dosing strategy based on PMA accounted for developmental changes in acyclovir disposition to achieve the surrogate pharmacodynamic target in many infants.

FIGURE 1

Final population PK model diagnostic plots. (A) Observed vs. population predictions; (B) observed vs. individual predictions; (C) conditional weighted residuals vs. population predictions; (D) conditional weighted residuals vs. time since first dose. A locally weighted scatterplot smoothing line was fit to the data points in C and D.

FIGURE 2

Standardized visual predictive check. Solid black circles: observed concentrations; dashed black lines: 5th, 50th, and 95th percentiles of predicted concentration.

FIGURE 3

Relationship between individual Bayesian PK parameter estimates and PMA. (A) Clearance; (B) half-life.