(Val)Ganciclovir TDM in Transplant Recipients

(Val)Ganciclovir Therapeutic Drug Monitoring in Transplant Recipients

The aim of this study is to gain more insight into therapeutic drug monitoring and thus the pharmacodynamics and pharmacokinetics of ganciclovir, in the context of prophylaxis and treatment of CMV infections, in order to provide the patient with an adequate dose.

Study Overview

• Status: Unknown
• Conditions: Cytomegalovirus Infections
• Intervention / Treatment: Drug: Ganciclovir; Drug: Valganciclovir

Detailed Description

Patients undergoing solid organ or stem cell transplantation are at risk of developing cytomegalovirus (CMV) infection or reactivation. The risk of CMV infection / reactivation and its severity depends on the CMV serostatus of donor and recipient. Valganciclovir (oral pro-drug of ganciclovir) prophylaxis is used to postpone CMV infection or reactivation to a later point in the post-transplantation.

CMV infection/reactivation does not always lead to clinical disease. Valganciclovir (oral) can be used when CMV DNA is detected in the blood, but patient has no or few complaints. However, in case of severe symptoms such as colitis, nephritis, hepatitis, pneumonitis, uveitis or encephalitis (active CMV disease) then ganciclovir is indicated intravenously. In clinical recovery treatment is often completed with valganciclovir.

It is important that the ganciclovir level is adequate, because too high level can lead to side effects such as cytopenia and a too low level can lead to treatment failure and resistance development. There are different dosing schedules mentioned in different sources. These schemes are based on dated literature.

The aim of (val)ganciclovir therapeutic drug monitoring (TDM) is to gain more insight into the pharmacodynamics and pharmacokinetics of ganciclovir, in the context of prophylaxis and treatment of CMV infections, in order to provide the patient with an adequate dose.

• Study Type: Observational
• Enrollment (Anticipated): 100

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands
    • Recruiting
    • UMCG
    • Contact: JWC Alffenaar, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients undergoing solid organ or stem cell transplantation are at risk of developing cytomegalovirus (CMV) infection or reactivation. Valganciclovir (oral pro-drug of ganciclovir) prophylaxis is used to postpone CMV infection or reactivation to a later point in the post-transplantation.

Description

Inclusion Criteria:

• Must receive ganciclovir intravenously or valganciclovir orally as routine care
• Must have received a solid organ or stem cell transplant
• Must be be 18 years or older

Exclusion Criteria:

There are no exclusion criteria.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Prophylaxis; Patients who receive (val)ganciclovir for prophylaxis of cytomegalovirus	Drug: Ganciclovir; Intravenous ganciclovir + TDM; Other Names: Cymevene; Drug: Valganciclovir; Oral valganciclovir + TDM; Other Names: Valcyte
Treatment; Patients who receive (val)ganciclovir for treatment of cytomegalovirus	Drug: Ganciclovir; Intravenous ganciclovir + TDM; Other Names: Cymevene; Drug: Valganciclovir; Oral valganciclovir + TDM; Other Names: Valcyte

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Failure of CMV treatment (with valganciclovir and ganciclovir) using viral load measurements and determining mutations in CMV kinase gene UL97 and DNA polymerase gene UL54	How many days to the development of failure of treatment? Failure of treatment is defined by increased viral load (measured in serum, whole blood, plasma in copies per mL and/or viral resistance (change of ganciclovir treatment to foscarnet treatment as a consequence, resistance is determined by resistance testing determining CMV kinase gene UL97 and DNA polymerase gene UL54 for mutations) or death due to CMV.	12 months after transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Breakthrough CMV infection during CMV prophylaxis with valganciclovir	Breakthrough CMV infection during prophylaxis with valganciclovir, time (days) to development of breakthrough CMV infection during prophylaxis	12 months after transplantation
Therapeutic window	How many levels are in and out of the therapeutic window (how many low and high levels)?	12 months after transplantation
Successful treatment while receiving (val)ganciclovir determined by two consequtive negative viral loads	The proportion of patients from CMV treatment group who have a successful CMV treatment, successful CMV treatment is defined by viral load <100 copies/mL (measured twice in a row).	12 months after transplantation
(Val)ganciclovir for treatment outcomes (1)	The proportion of patients from CMV treatment group who are under-dosed	12 months after transplantation
(Val)ganciclovir for treatment outcomes (2)	The proportion of patients from CMV treatment group who develop resistance to ganciclovir	12 months after transplantation
Factors that can influence trough concentrations of (val)ganciclovir (1)	Does the type of transplanted organ (liver, lungs, kidney, heart, stem cell transplant) cause high or low (val)ganciclovir trough concentrations (mg/L)? Defined therapeutic window for prophylaxis is 1-2 mg/L and for therapy is 2-4 mg/L. Number of levels which are out of the therapeutic window for different transplants.	12 months after transplantation
Factors that can influence trough concentrations of (val)ganciclovir (2)	Does the underlying disease for transplantation cause high or low (val)ganciclovir trough concentrations (mg/L)? Defined therapeutic window for prophylaxis is 1-2 mg/L and for therapy is 2-4 mg/L. Number of levels which are out of the therapeutic window for different underlying diseases.	12 months after transplantation
Factors that can influence trough concentrations of (val)ganciclovir (3)	Does dose reduction for renal failure cause increase or decrease in (val)ganciclovir trough concentrations (mg/L)? Number of levels which are out of the therapeutic window after dose reduction.	12 months after transplantation

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Investigators: Principal Investigator: Jan-Willem Alffenaar, PhD, University Medical Center Groningen

Study record dates

Study Major Dates

• Study Start (Actual): May 25, 2018
• Primary Completion (Anticipated): November 30, 2019
• Study Completion (Anticipated): December 31, 2019

Study Registration Dates

• First Submitted: February 7, 2018
• First Submitted That Met QC Criteria: October 3, 2018
• First Posted (Actual): October 9, 2018

Study Record Updates

• Last Update Posted (Actual): October 10, 2019
• Last Update Submitted That Met QC Criteria: October 8, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: pharmacokinetics; valganciclovir; ganciclovir; therapeutic drug monitoring
• Additional Relevant MeSH Terms: Virus Diseases; Infections; DNA Virus Infections; Herpesviridae Infections; Cytomegalovirus Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Valganciclovir; Ganciclovir; Ganciclovir triphosphate
• Other Study ID Numbers: 201800021

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No