Population Pharmacokinetics of Intravenous Acyclovir in Oncologic Pediatric Patients

Natalia Maximova; Daniela Nisticò; Giacomo Luci; Roberto Simeone; Elisa Piscianz; Ludovica Segat; Egidio Barbi; Antonello Di Paolo

doi:10.3389/fphar.2022.865871

Population Pharmacokinetics of Intravenous Acyclovir in Oncologic Pediatric Patients

Front Pharmacol. 2022 Apr 14:13:865871. doi: 10.3389/fphar.2022.865871. eCollection 2022.

Authors

Natalia Maximova¹, Daniela Nisticò², Giacomo Luci³, Roberto Simeone⁴, Elisa Piscianz⁵, Ludovica Segat⁵, Egidio Barbi^{1

2}, Antonello Di Paolo³

Affiliations

¹ Department of Pediatrics, Institute for Maternal and Child Health-IRCCS Burlo Garofolo, Trieste, Italy.
² Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
³ Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
⁴ Transfusion Medicine Department, Azienda Sanitaria Universitaria "Giuliano Isontina", Trieste, Italy.
⁵ Laboratory for Hygiene and Public Health, University Hospital of Trieste, Trieste, Italy.

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.