Optimization of Ganciclovir use in allogeneic hematopoietic cell transplant recipients – the role of therapeutic drug monitoring

ABSTRACT

Introduction: Cytomegalovirus (CMV) is an opportunistic infectious complication that can occur after allogeneic hematopoietic cell transplantation (HCT). The mainstay of treatment and prevention of this infection is ganciclovir and its ester prodrug valganciclovir. There is conflicting evidence on the clinical utility of routine ganciclovir therapeutic drug monitoring (TDM) as a means to optimize treatment.

Areas covered: This review aims to describe the current knowledge of the pharmacokinetic and pharmacodynamic characteristics of ganciclovir and valganciclovir, and to explore the evidence and challenges surrounding ganciclovir TDM within the allogeneic HCT cohort.

Expert opinion: Ganciclovir TDM is important to optimize efficacy in selected patient groups where there are variable pharmacokinetic factors or inadequate response to treatment. However, defined pharmacokinetic exposures which correlate with treatment efficacy and toxicity remain elusive. Prospective clinical studies in specific patient groups are required to clarify this issue. Alternative TDM targets such as the intracellular ganciclovir triphosphate should be explored as they may prove to have better correlation with clinical outcomes and adverse effects. With recent advances in CMV immune monitoring, novel approaches integrating TDM with specific CMV immune phenotyping in a predictive model will be advantageous in optimizing ganciclovir dosing by combining TDM with a risk stratification approach.

KEYWORDS:

• Allogeneic
• CMV
• ganciclovir
• TDM
• valganciclovir

Acknowledgments

J.A. Roberts would like to acknowledge funding from the Australian National Health and Medical Research Council for a Centre of Research Excellence (APP1099452) and a Practitioner Fellowship (APP1117065). The authors wish to thank Dr Nyein Chan Aung for his illustration.

Article highlights

• The activity of ganciclovir is determined by the susceptibility of the specific viral strain in the individual patient and intracellular concentration of the active compound.

• Ganciclovir dosing algorithms result in highly variable interindividual concentrations despite recommended adjustments according to body weight and renal function.

• There is little consensus on a therapeutic range which correlates with clinical outcomes and toxicity, with individual institutions extrapolating results from either in vitro studies or earlier studies performed in AIDS patients and the renal transplant group.

• Ganciclovir TDM may be beneficial in select patient groups, namely, those with highly variable pharmacokinetic profiles such as patients with fluctuating renal function and the pediatric population, and to minimize the risk of drug-related hematological toxicity.

• Future studies should investigate novel approaches to ganciclovir TDM with more specific measures of antiviral activity such as intracellular ganciclovir concentrations, host CMV specific T-cell functional immune markers and pharmacogenomic screening to provide more accurate reflection of the anti-CMV activity.

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.