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A Systematic Review of the Clinical Pharmacokinetics, Pharmacodynamics and Toxicodynamics of Ganciclovir/Valganciclovir in Allogeneic Haematopoietic Stem Cell Transplant Patients

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Abstract

Background

Ganciclovir (GCV) and valganciclovir (VGCV) are the first-line agents used to prevent and treat cytomegalovirus (CMV) infection in allogeneic haematopoietic stem cell transplant (alloHCT) patients.

Objective

The aim of this work was to describe available data for the clinical pharmacokinetics, pharmacodynamics and toxicodynamics of GCV and VGCV and the potential of a therapeutic drug monitoring strategy to improve outcomes in the alloHCT population.

Methods

We systematically reviewed the pharmacokinetics (dose-exposure), pharmacodynamics (exposure-efficacy) and toxicodynamics (exposure-toxicity) of GCV and VGCV in alloHCT patients with CMV infection. Studies including alloHCT patients treated for CMV infection reporting the pharmacokinetics, pharmacodynamics and toxicodynamics of GCV or VGCV were searched for using the PUBMED and EMBASE databases from 1946 to 2019. Only studies involving participants > 12 years of age and available in the English language were included.

Results

A total of 179 patients were included in the 14 studies that met the inclusion criteria, of which 6 examined GCV pharmacokinetics only, while 8 also examined GCV pharmacodynamics and toxicodynamics. Reported pharmacokinetic parameters showed considerable interpatient variability and were different from other populations, such as solid organ transplant and human immunodeficiency virus-infected patients. Only one study found a correlation between neutropenia and elevated peak and trough GCV concentrations, with no other significant pharmacodynamic and toxicodynamic relationships identified. While therapeutic drug monitoring of GCV is performed in some institutions, no association between GCV therapeutic drug monitoring and clinical outcomes was identified.

Conclusion

Further studies of the pharmacokinetics, pharmacodynamics and toxicodynamics of GCV/VGCV in alloHCT patients are required to identify a more robust therapeutic range and to subsequently quantify the potential value of therapeutic drug monitoring of GCV/VGCV in the alloHCT population.

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Authors and Affiliations

  1. School of Medicine, University of Adelaide, Adelaide, SA, Australia

    Philip Roland Selby, Sepehr Shakib, Sandra L. Peake, Morgyn S. Warner, David Yeung & Uwe Hahn

  2. Pharmacy Department, Royal Adelaide Hospital, Port Road, Adelaide, SA, 5000, Australia

    Philip Roland Selby

  3. Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, SA, Australia

    Sepehr Shakib

  4. Department of Intensive Care Medicine, The Queen Elizabeth Hospital, Adelaide, SA, Australia

    Sandra L. Peake

  5. Infectious Diseases Unit, The Queen Elizabeth Hospital, Adelaide, SA, Australia

    Morgyn S. Warner

  6. SA Pathology, Adelaide, SA, Australia

    Morgyn S. Warner, David Yeung & Uwe Hahn

  7. Haematology Unit, Royal Adelaide Hospital, Adelaide, SA, Australia

    David Yeung & Uwe Hahn

  8. Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia

    David Yeung

  9. Faculty of Medicine and Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, University of Queensland Centre for Clinical Research (UQCCR), The University of Queensland, St Lucia, QLD, Australia

    Jason A. Roberts

  10. Departments of Pharmacy and Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia

    Jason A. Roberts

  11. Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France

    Jason A. Roberts

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Correspondence to Philip Roland Selby.

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Funding

Philip R. Selby is the recipient of an Australian Government Research Training Program Scholarship.

Conflict of interest

Philip R. Selby has received financial support from Merck Sharp & Dohme to attend symposia. David Yeung has received honoraria from Novartis, Bristol Myers Squibb, Pfizer, Amgen and Takeda, and research funding from Novartis and Bristol Myers Squibb. Jason A. Roberts has received grants, consultancies or speaker fees from Biomerieux, Merck Sharp & Dohme, Discuva, Accelerate Diagnostics, The Medicines Company, Qpex and Pfizer. Sepehr Shakib, Sandra L. Peake, Morgyn S. Warner and Uwe Hahn have no conflicts of interest to declare.

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Authors’ contributions

PS, SS, MW and JR conceived the presented idea. PS and SS undertook the database search, determined study eligibility for the review and extracted the relevant data from the studies for review. PS, SS, SP, MW, DY, UH and JR evaluated and interpreted the included studies. PR wrote the first draft of the manuscript and critical revision was undertaken by SS, SP, MW, DY, UH and JR. All authors read and approved the final version of the manuscript.

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Selby, P.R., Shakib, S., Peake, S.L. et al. A Systematic Review of the Clinical Pharmacokinetics, Pharmacodynamics and Toxicodynamics of Ganciclovir/Valganciclovir in Allogeneic Haematopoietic Stem Cell Transplant Patients. Clin Pharmacokinet 60, 727–739 (2021). https://doi.org/10.1007/s40262-020-00982-z

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