Optimizing ganciclovir and valganciclovir dosing regimens in pediatric patients with cytomegalovirus infection: a spotlight on therapeutic drug monitoring

ABSTRACT

Introduction

Infants and immunocompromised children with cytomegalovirus (CMV) infection have significant morbidity and mortality. Ganciclovir (GCV) and its oral prodrug valganciclovir (VGCV) are the major antiviral options of choice for the prophylaxis and treatment of CMV infection. However, with the currently recommended dosing regimens used in pediatric patients, large intra- and inter-individual variability of pharmacokinetic (PK) parameters and exposure are observed.

Areas covered

This review describes the PK and pharmacodynamic (PD) characteristics of GCV and VGCV in pediatrics. Moreover, the role of therapeutic drug monitoring (TDM) and current clinical practice for GCV and VGCV dosing regimens optimization in pediatrics are discussed.

Expert opinion

GCV/VGCV TDM has shown the potential value to improve the benefit/risk ratio in pediatrics when using the therapeutic ranges derived from adults. However, well-designed studies are required to evaluate the relationship of TDM with clinical outcomes. Furthermore, studies to explore the children-specific dose-response-effect relationships will be helpful to facilitate the TDM practice. In the clinical setting, optimal sampling methods such as limited sampling strategies for pediatrics can be used in TDM and intracellular ganciclovir triphosphate may be used as an alternative TDM marker.

KEYWORDS:

• Cytomegalovirus
• ganciclovir
• valganciclovir
• pediatric
• therapeutic drug monitoring
• individualized therapy

Article highlights

• Current dosage regimens of ganciclovir and valganciclovir result in high interindividual variability and a low probability of therapeutic exposure attainment in pediatric patients.

• The currently widely used target therapeutic range of GCV for children is extrapolated from adults. Well-designed studies are required to evaluate the relationship between TDM using the adult therapeutic range and clinical efficacy and toxicity in children.

• Therapeutic drug monitoring of GCV/VGCV is a potentially attractive method for children to ensure efficacy and minimize toxicity if the pediatric-specific target exposure is well established.

• Traditional TDM sampling method causes a burden for children and parents, whereas Bayesian methods based on limited sampling strategies allow minimal blood sampling and flexible sampling time to predict AUC precisely.

• Model-based simulation and prediction provide a clinically feasible method for GCV and VGCV dose individualization, but these dosage regimens should be prospectively validated.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper is funded by the National Natural Science Foundation of China (82173897), Distinguished Young and Middle-aged Scholar of Shandong University, Innovation and Development Joint Fund of Natural Science Foundation of Shandong Province (ZR2022LSW007) and Natural Science Foundation of Shandong Province (ZR2022QH004).