Population Pharmacokinetics of Intravenous Acyclovir in Oncologic Pediatric Patients

Abstract

Background: Acyclovir represents the first-line prophylaxis and therapy for herpes virus infections. However, its pharmacokinetics in children exposes them to the risk of ineffective or toxic concentrations. The study was aimed at investigating the population pharmacokinetics (POP/PK) of intravenous (IV) acyclovir in oncologic children. Methods: Patients (age, 8.6 ± 5.0 years, 73 males and 47 females) received IV acyclovir for prophylaxis (n = 94) and therapy (n = 26) under a therapeutic drug monitoring (i.e., minimum and maximal plasma concentrations, >0.5 and <25 mg/L, respectively). Plasma concentrations were fitted by nonlinear mixed effect modeling and a simulation of dosing regimens was performed. Findings were stratified according to an estimated glomerular filtration rate (eGFR) threshold of 250 ml/min/1.73 m2. Results: The final 1-compartment POP/PK model showed that eGFR had a significant effect on drug clearance, while allometric body weight influenced both clearance and volume of distribution. The population clearance (14.0 ± 5.5 L/h) was consistent across occasions. Simulation of standard 1-h IV infusion showed that a 10-mg/kg dose every 6 h achieved target concentrations in children with normal eGFR (i.e., ≤250 ml/min/1.73 m2). Increased eGFR values required higher doses that led to an augmented risk of toxic peak concentrations. On the contrary, simulated prolonged (i.e., 2 and 3-h) or continuous IV infusions at lower doses increased the probability of target attainment while reducing the risk of toxicities. Conclusion: Due to the variable pharmacokinetics of acyclovir, standard dosing regimens may not be effective in some patients. Prospective trials should confirm the therapeutic advantage of prolonged and continuous IV infusions.

Keywords: acyclovir; children; hematopoietic stem cell transplantation; non-linear mixed effect modeling; pediatric patients; pharmacokinetics; prolonged infusion; prolonged infusion acyclovir.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Maximova, Nisticò, Luci, Simeone, Piscianz, Segat, Barbi and Di Paolo.

Figures

FIGURE 1

Characteristics of the 120 enrolled patients: initial diagnosis (A), first-line therapy (B), and reasons for acyclovir administration (C). Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloblastic leukemia; MDS, myelodysplastic syndrome; HSCT, hematopoietic stem cell transplantation.

FIGURE 2

Box-and-whiskers plot of single measured plasma concentrations of acyclovir 30 min after the end of the infusion (1.5 h) and 10 min before the next dose in 6-h (5.83 h) and 8-h (7.83 h) regimens.

FIGURE 3

Goodness-of-fit plots. Population (A) and individual (B) prediction values vs. observations. (C), absolute values of individual weighted residuals (iWRES) error vs. individual predictions and (D) conditional weighted residuals vs. time. Symbols, individual plasma concentrations of acyclovir. Red lines, regression, and Loess lines. Black line, line of identity.

FIGURE 4

The prediction-corrected visual predictive check based on the present data. Open circles, individual plasma concentrations of acyclovir together with their median and 5th-95th percentiles (solid and dashed red lines, respectively). The 95% confidence intervals of the simulated median (pale pink) and 5th-95th percentiles (pale blue) are showed.

FIGURE 5

Simulated regimens consisting in ACV 20 or 25 mg/kg administered as 1-h, 2-h and 3-h infusion every 6 h [graphs (A,C)] and 8 h [graphs (B,D)]. Plots show the probability of target attainment (on the left) according to Cmin values < 0.56 (grey), ≥0.56-<1.125 (pale blue) and >1.125 mg/L (blue). Moreover, graphs show the probability of achieving Cmax values < 25 (pale blue) and >25 mg/L (red).