Advertisement

Clinical Pharmacokinetics

, Volume 57, Issue 11, pp 1399–1405 | Cite as

Valganciclovir Pharmacokinetics in Patients Receiving Oral Prophylaxis Following Kidney Transplantation and Model-Based Predictions of Optimal Dosing Regimens

  • Thomas Tängdén
  • Pier Giorgio Cojutti
  • Jason A. Roberts
  • Federico Pea
Original Research Article

Abstract

Background and Objectives

Valganciclovir is used as oral prophylaxis for cytomegalovirus (CMV) infection in kidney transplant recipients. However, limited pharmacokinetic data exist to guide dosing in this patient group. This study aimed to describe the population pharmacokinetics of valganciclovir in a large sample of kidney transplant recipients and predict optimal dosing based on Monte Carlo simulations.

Methods

Therapeutic drug monitoring (TDM) data from adult kidney transplant recipients who received valganciclovir prophylaxis during a 10-year study period were collected retrospectively. A non-parametric pharmacokinetic analysis and Monte Carlo simulations to determine the probabilities of reaching an area under the drug concentration–time curve (AUC) target of 40–50 mg·h/L with various dosing regimens at different levels of renal function were conducted using the Pmetrics™ package for R.

Results

This study included 792 ganciclovir concentration measurements derived from 97 patients. A one-compartment oral absorption model best described the data. The final covariate model was as follows: CL(ganciclovir) = TVCL × (CLCR/51)0.75, where CL is the clearance, TVCL is the typical value of ganciclovir clearance, creatinine clearance (CLCR) according to the Cockcroft-Gaultt equation and 51 is the mean CLCR determined in the study. In the simulations, the probability of reaching the targeted AUC was insufficient when using the recommended dosing regimens for prophylaxis, especially in patients with impaired renal function at CLCR < 50 mL/min.

Conclusions

Higher doses of valganciclovir corrected to renal function are suggested for use as oral prophylaxis for CMV infection in kidney transplant recipients. Further study is required to establish TDM targets to ensure adequate drug concentrations while avoiding potentially toxic drug exposures.

Notes

Compliance with Ethical Standards

Funding

This work was supported by internal funding. We wish to recognise funding from the Australian National Health and Medical Research Council for a Centre of Research Excellence (APP1099452). JAR is funded in part by a Practitioner Fellowship (APP1117065) from the National Health and Medical Research Council of Australia.

Conflict of interest

Thomas Tängdén, Pier Giorgio Cojutti and Federico Pea declare no conflicts of interest. Jason A. Roberts has received investigator-initiated grants from, or has consulted for, bioMérieux, Astellas, MSD and Cardeas Pharma.

Supplementary material

40262_2018_638_MOESM1_ESM.tiff (7.9 mb)
Supplementary material 1 (TIFF 8106 kb)

References

  1. 1.
    Cvetković RS, Wellington K. Valganciclovir: a review of its use in the management of CMV infection and disease in immunocompromised patients. Drugs. 2005;5:859–78.CrossRefGoogle Scholar
  2. 2.
    Lowance D, Neumayer HH, Legendre CM, et al. Valganciclovir for the prevention of cytomegalovirus disease after renal transplantation. N Engl J Med. 1999;340:1462–70.CrossRefPubMedGoogle Scholar
  3. 3.
    Jung D, Dorr A. Single-dose pharmacokinetics of valganciclovir agents for solid organ transplantation. J Clin Pharmacol. 1999;39:800–4.CrossRefPubMedGoogle Scholar
  4. 4.
    Pescovitz MD, Rabkin J, Merion RM, et al. Valganciclovir results in improved oral absorption of ganciclovir in liver transplant recipients. Antimicrob Agents Chemother. 2000;44:2811–5.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    McGavin JK, Goa KL. Ganciclovir: an update of its use in the prevention of cytomegalovirus infection and disease in transplant recipients. Drugs. 2001;61:1153–83.CrossRefPubMedGoogle Scholar
  6. 6.
    Wiltshire H, Paya CV, Pescovitz MD, et al. Pharmacodynamics of oral ganciclovir and valganciclovir in solid organ transplant recipients. Transplantation. 2005;79:1477–83.CrossRefPubMedGoogle Scholar
  7. 7.
    Caldés A, Colom H, Armendariz Y, et al. Population pharmacokinetics of ganciclovir after intravenous ganciclovir and oral valganciclovir administration in solid organ transplant patients infected with cytomegalovirus. Antimicrob Agents Chemother. 2009;53:4816–24.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Yuen GJ, Drusano GL, Fletcher C, et al. Population differences in ganciclovir clearance as determined by nonlinear mixed-effects modelling. Antimicrob Agents Chemother. 1995;39:2350–2.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Perrottet N, Decosterd LA, Meylan P, Pascual M, Biollaz J, Buclin T. Valganciclovir in adult solid organ transplant recipients: pharmacokinetic and pharmacodynamic characteristics and clinical interpretation of plasma concentration measurements. Clin Pharmacokinet. 2009;48:399–418.CrossRefPubMedGoogle Scholar
  10. 10.
    Boulieu R, Bleyzac N, Ferry S. High-performance liquid chromatographic determination of ganciclovir in plasma. J Chromatogr. 1991;567:481–4.CrossRefPubMedGoogle Scholar
  11. 11.
    Tatarinova T, Neely M, Bartroff J, et al. Two general methods for population pharmacokinetic modeling: non-parametric adaptive grid and non-parametric Bayesian. J Pharmacokinet Pharmacodyn. 2013;40:189–99.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Neely M, van Guilder M, Yamada W, Schumitzky A, Jelliffe R. Accurate detection of outliers and subpopulations with Pmetrics, a non-parametric and parametric pharmacometric modeling and simulation package for R. Ther Drug Monit. 2012;34:467.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.CrossRefGoogle Scholar
  14. 14.
    Levey AS, Stevens AL, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–12.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Mentré F, Escolano S. Prediction discrepancies for the evaluation of nonlinear mixed-effects models. J Pharmacokinet Pharmacodyn. 2006;33:345–67.CrossRefPubMedGoogle Scholar
  16. 16.
    Padullés A, Colom H, Bestard O, et al. Contribution of population pharmacokinetics to dose optimization of ganciclovir in solid organ transplant patients. Antimicrob Agents Chemother. 2016;60:1992–2002.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Vezina H, Brundage RC, Balfour HH. Population pharmacokinetics of valganciclovir prophylaxis in paediatric and adult solid organ transplant recipients. Br J Clin Pharmacol. 2014;78:343–52.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Thomas Tängdén
    • 1
  • Pier Giorgio Cojutti
    • 2
    • 3
  • Jason A. Roberts
    • 4
    • 5
  • Federico Pea
    • 2
    • 3
  1. 1.Department of Medical SciencesUppsala UniversityUppsalaSweden
  2. 2.Institute of Clinical PharmacologySanta Maria della Misericordia University, ASUIUDUdineItaly
  3. 3.Department of MedicineUniversity of UdineUdineItaly
  4. 4.Departments of Intensive Care Medicine and PharmacyRoyal Brisbane and Women’s HospitalBrisbaneAustralia
  5. 5.University of Queensland Centre for Clinical Research, Faculty of Medicine and Centre for Anti-infective Translational Pharmacodynamics, School of PharmacyThe University of QueenslandHerstonAustralia

Personalised recommendations