Ignite Creation Date:
2024-05-06 @ 1:15 AM
Last Modification Date:
2024-10-26 @ 11:01 AM
Study NCT ID:
NCT01767350
Status:
COMPLETED
Last Update Posted:
2015-12-15
First Post:
2013-01-10
Brief Title:
Determinants of Immunosuppressive Dose Requirements in Children After Solid Organ Transplantation
Sponsor:
Universitaire Ziekenhuizen KU Leuven
Organization:
Universitaire Ziekenhuizen KU Leuven
Study Overview
Official Title:
Study Aimed at Determining the Relation Between the Administered Dose and Exposure to Immunosuppressive Medication in Children After Solid Organ Transplantation
Status:
COMPLETED
Status Verified Date:
2015-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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
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
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 metabolismCYP3A4 CYP3A5 MDR1 which were associated with differences in dosing and toxicity 4-10 In particular carriers of a common polymorphism in CYP3A5 designated CYP3A51 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 27 fold higher for patients under 5 years and 19 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 CYP3A45 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 andor 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 hospitaloutpatient 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
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 metabolismCYP3A4 CYP3A5 MDR1 which were associated with differences in dosing and toxicity 4-10 In particular carriers of a common polymorphism in CYP3A5 designated CYP3A51 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 27 fold higher for patients under 5 years and 19 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 CYP3A45 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 andor 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 hospitaloutpatient 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None