Population Pharmacokinetics of Intravenous and Oral Acyclovir and Oral Valacyclovir in Pediatric Population To Optimize Dosing Regimens

Abstract

Acyclovir is an antiviral currently used for the prevention and treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. This study aimed to characterize the pharmacokinetics (PK) of acyclovir and its oral prodrug valacyclovir to optimize dosing in children. Children receiving acyclovir or valacyclovir were included in this study. PK were described using nonlinear mixed-effect modeling. Dosing simulations were used to obtain trough concentrations above a 50% inhibitory concentration for HSV or VZV (0.56 mg/liter and 1.125 mg/liter, respectively) and maximal peak concentrations below 25 mg/liter. A total of 79 children (212 concentration-time observations) were included: 50 were taking intravenous (i.v.) acyclovir, 22 were taking oral acyclovir, and 7 were taking both i.v. and oral acyclovir, 57 for preventive and 22 for curative purposes. A one-compartment model with first-order elimination best described the data. An allometric model was used to describe body weight effect, and the estimated glomerular filtration rate (eGFR) was significantly associated with acyclovir elimination. To obtain target maximal and trough concentrations, the more suitable initial acyclovir i.v. dose was 10 mg/kg of body weight/6 h for children with normal renal function (eGFR ≤ 250 ml/min/1.73 m2) and 15 to 20 mg/kg/6 h for children with augmented renal clearance (ARC) (eGFR > 250 ml/min/1.73 m2). The 20-mg/kg/8 h dose for oral acyclovir and valacyclovir produced effective concentrations in more than 75% of children; however, a 15-mg/kg/6 h dose, if possible, is preferred. These doses should be prospectively confirmed, and therapeutic drug monitoring could be used to refine them individually. (This study has been registered at ClinicalTrials.gov under identifier NCT02539407.).

Keywords: antiviral agents; children; population pharmacokinetics.

Copyright © 2020 American Society for Microbiology.

Figures

FIG 1

Acyclovir concentrations as a function of time after dose of acyclovir i.v. (black circles), oral acyclovir (blue circles), and oral valacyclovir (red circles).

FIG 2

Pharmacokinetic compartmental model for acyclovir plasma concentration after oral or i.v. dose D. F, bioavailability of acyclovir; ka, first-order absorption rate constant; V, acyclovir distribution volume; ke, acyclovir elimination rate constant.

FIG 3

(Upper graphs) Observation data versus population predictions (upper left) and versus individual predictions (upper right) in the final model, after doses of acyclovir i.v. (black circles), oral acyclovir (blue circles), and oral valacyclovir (red circles). The solid black line is the identity line. (Lower graphs) Normalized prediction distribution error (npde) versus time (lower left) and predictions (lower right), after doses of acyclovir i.v. (black circles), oral acyclovir (blue circles), and oral valacyclovir (red circles). The solid horizontal line is the theoretical mean (0), and the dashed line corresponds to regression.

FIG 4

Prediction-corrected visual predictive check for acyclovir concentrations, following an i.v. acyclovir dose in linear scale (left) and in log-linear scale (middle) and an oral valacyclovir dose in linear scale (right). Colored areas represent 95% confidence intervals (CIs) of 5th, 95th (dark grey), and 50th (light grey) simulated percentiles. Lines indicate empirical (observed) 5th, 50th, and 95th percentiles. Dots represent observed data.

FIG 5

Simulations of trough (Ctrough) and peak (Cmax) concentrations according to the route of administration (i.v. or oral) and renal function (eGFR of <250 or >250 ml/min/1.73 m2). Color code: red, Cmax of >25 mg/liter; green, Ctrough of >1.125 mg/liter and Cmax of <25 mg/liter; yellow, Ctrough of <1.125 mg/liter and Cmax of <25 mg/liter; orange, Ctrough of <0.56 mg/liter and Cmax of <25 mg/liter.