Determinants of Immunosuppressive Dose Requirements in Children After Solid Organ Transplantation

December 14, 2015 updated by: Noël Knops, Universitaire Ziekenhuizen KU Leuven

Study Aimed at Determining the Relation Between the Administered Dose and Exposure to Immunosuppressive Medication in Children After Solid Organ Transplantation

The long-term success of solid organ transplantation is largely dependent on the efficacy of immunosuppressive medication. Unfortunately, for the most important agents the correct drug levels are difficult to attain, with potential severe consequences of drug under- or overexposure. In addition there is a large variation in dose requirements within and between different subjects. Clinical studies have demonstrated that a better control of drug exposure can improve outcome. A large set of patient characteristics appear important in determining dose requirements in adults, in particular genetic variation in genes involved in drug metabolism. In children relative dose requirements are increased compared to adults, but is not known why and the role of pharmacogenetic variation has not been described.

Our study aims to describe relative dose requirements in children after solid organ transplantation with the help of clinical and laboratory data obtained during regular hospital visits (retrospective). In addition we will assess their genotype for genes involved in the metabolism of immunosuppressives.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The success of solid organ transplantation is for an important part determined by the potency of the immunosuppressive regime to prevent allograft rejection. Depending on the type of organ transplanted current 5-year graft survival for liver is circa 70% and for kidney almost 80% (1-3). Although acute rejection has become less a problem, analyses of data on the follow-up of solid organ recipients has demonstrated that long-term allograft survival has not improved much in the last decade. The life expectancy of a donor organ appears limited due to phenomena such as chronic, antibody mediated, rejection and the toxic effects of immunosuppressive medication.

Unfortunately, the most commonly applied immunosuppressive agents (in particular the calcineurin-inhibitors) possess a narrow therapeutic index with potential severe consequences of drug under- or overexposure. Furthermore, in clinical practice optimal dosing is difficult to achieve due to important inter- and intraindividual variation in drug pharmacokinetics. Consequently attention has shifted towards designing a "tailored immunosuppressive maintenance therapy", aimed at optimization of drug efficacy and the prevention of these unintended and possible deleterious side effects in the individual recipient. For a "perfect fit" this entails a fundamental knowledge of the individual characteristics of the recipient and its graft in relation to the pharmacodynamic and -kinetic properties of the agent.

A complex and often interdependent set of factors appears relevant in determining drug exposure. These include recipient characteristics such as age, race, body composition, organ function (intestine-liver-kidney), food and concomitant medication intake, but also graft-related characteristics such as: seize, donor-age, and time after transplantation. Longitudinal and cross-sectional analysis of clinical and genetic co-variables in allograft recipient cohorts has identified several single nucleotide polymorphisms (SNPs) in genes encoding for enzymes and transporters involved in drug metabolism(CYP3A4, CYP3A5, MDR1), which were associated with differences in dosing and toxicity (4-10). In particular carriers of a common polymorphism in CYP3A5 (designated CYP3A5*1) demonstrate a 25-40% increase in tacrolimus clearance and a 2-3 fold increase in dose requirements.

In children the dose requirements per kg bodyweight to attain desired blood concentrations are approximately 2.7 fold higher for patients under 5 years and 1.9 fold higher for patients aged 5 to 12 years when compared to older patients11-14. Age-related differences in expression of enzymes or transporters involved in drug metabolism might play an important role. Fakhoury et al demonstrated an increase in intestinal CYP3A4/5 mRNA and protein expression from childhood to adulthood (15). In addition other factors such as intestinal transit time and length, body composition, protein binding, body metabolism and organ function, might be important in determining dose requirements in children (16-18). The importance of the aforementioned genetic polymorphisms on long-term dose requirements have not been studied in children.

Objective:

To describe dose requirements of immunosuppressive medication in relation to a set of clinical and non-clinical (genetic) factors in a cohort of pediatric recipients of a solid organ allograft.

Methods:

A retrospective study in a single center (University Hospitals Leuven) with an active program for pediatric kidney, liver and intestinal transplantation. The study population consists of subjects who received a solid organ transplant (liver, kidney, intestine, combined) between 0 and 18 years of age.

As a part of their standard care patients are admitted to the department for a yearly check-up after transplantation. During this admission a set of investigations are performed to evaluate the current medical situation, including an elaborate pharmacokinetic (PK) assessment. Patient characteristics and clinical data (age, bodyweight, sex, type of graft, cause of organ failure, co-medication, laboratory results, PK data) will be retrieved from the patient files concerning these follow-up admissions. In addition patients and/or their parents will be requested permission to collect one extra tube of whole blood (ca 8 ml) for DNA analysis during a standard blood collection at a regular hospital/outpatient visit.

After collection patient data will be given a code for further anonymous storage and analysis. DNA SNP analysis will take place at our laboratory for pediatric nephrology with PCR.

Study Type

Observational

Enrollment (Actual)

60

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Belgium
      • Leuven, Belgium, 3000
        • University Hospitals Leuven

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 30 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Pediatric recipients of a solid organ transplantation

Description

Inclusion Criteria:

  • All pediatric recipients of a solid organ transplantation in our hospital
  • Extensive pharmacokinetic study of immunosuppression (AUC) performed during follow up
  • Consent of child/caretaker

Exclusion Criteria:

-

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
children with organ transplant
Subjects who received an solid organ transplant at our institution at the age of 0-19 yrs and who were subject to pharmacokinetic evaluation during their follow up. Additional blood withdrawal for DNA will be performed
Procedure: Blood withdrawal for DNA
Single withdrawal of 8 ml whole blood for DNA analysis, during a "standard" blood collection as part of standard clinical follow up.
Other Names:
  • not applicalble

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Relative dose requirement of tacrolimus, ciclosporin or MMF
Time Frame: 1 yr
analysis of retrospective data concerning pharmacokinetic assessment as part of standard clinical care
1 yr

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pharmacogenetic genotype
Time Frame: 1 yr
Analysis of DNA obtained during a regular hospital visit for genetic variants relevant for metabolism of immunosuppression according to literature (CYP3A4, CYP3A5, MDR1, etc)
1 yr

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Universitaire Ziekenhuizen KU Leuven

Investigators

  • Principal Investigator: Noel Knops, MD, Universitaire Ziekenhuizen KU Leuven

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2013

Primary Completion (Actual)

January 1, 2015

Study Completion (Actual)

January 1, 2015

Study Registration Dates

First Submitted

January 10, 2013

First Submitted That Met QC Criteria

January 10, 2013

First Posted (Estimate)

January 14, 2013

Study Record Updates

Last Update Posted (Estimate)

December 15, 2015

Last Update Submitted That Met QC Criteria

December 14, 2015

Last Verified

December 1, 2015

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • S55088

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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