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Determinants of Immunosuppressive Dose Requirements in Children After Solid Organ Transplantation

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01767350
First Posted: January 14, 2013
Last Update Posted: December 15, 2015
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Noël Knops, Universitaire Ziekenhuizen Leuven
  Purpose

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.


Condition Intervention
Transplantation Infection Procedure: Blood withdrawal for DNA

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Retrospective
Official Title: Study Aimed at Determining the Relation Between the Administered Dose and Exposure to Immunosuppressive Medication in Children After Solid Organ Transplantation

Resource links provided by NLM:


Further study details as provided by Noël Knops, Universitaire Ziekenhuizen Leuven:

Primary Outcome Measures:
  • 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


Secondary Outcome Measures:
  • 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)


Biospecimen Retention:   Samples With DNA
tube of whole blood (8 ml) to be processed for DNA extraction and storage

Enrollment: 60
Study Start Date: February 2013
Study Completion Date: January 2015
Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
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 Name: not applicalble

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Pediatric recipients of a solid organ transplantation
Criteria

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:

  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01767350


Locations
Belgium
University Hospitals Leuven
Leuven, Belgium, 3000
Sponsors and Collaborators
Universitaire Ziekenhuizen Leuven
Investigators
Principal Investigator: Noel Knops, MD University Hospitals Leuven
  More Information

Publications:
Cai J, Terasaki PI. Induction immunosuppression improves long-term graft and patient outcome in organ transplantation: an analysis of United Network for Organ Sharing registry data. Transplantation. 2010 Dec 27;90(12):1511-5. doi: 10.1097/TP.0b013e3181fecfcb.
Opelz G, Süsal C, Ruhenstroth A, Döhler B. Impact of HLA compatibility on lung transplant survival and evidence for an HLA restriction phenomenon: a collaborative transplant study report. Transplantation. 2010 Oct 27;90(8):912-7. doi: 10.1097/TP.0b013e3181f2c981.
Opelz G, Döhler B; Collaborative Transplant Study. Influence of immunosuppressive regimens on graft survival and secondary outcomes after kidney transplantation. Transplantation. 2009 Mar 27;87(6):795-802. doi: 10.1097/TP.0b013e318199c1c7.
Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I. Clin Pharmacokinet. 2010 Mar;49(3):141-75. doi: 10.2165/11317350-000000000-00000. Review.
Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part II. Clin Pharmacokinet. 2010 Apr;49(4):207-21. doi: 10.2165/11317550-000000000-00000. Review.
de Jonge H, Kuypers DR. Pharmacogenetics in solid organ transplantation: current status and future directions. Transplant Rev (Orlando). 2008 Jan;22(1):6-20. doi: 10.1016/j.trre.2007.09.002. Review.
de Jonge H, Naesens M, Kuypers DR. New insights into the pharmacokinetics and pharmacodynamics of the calcineurin inhibitors and mycophenolic acid: possible consequences for therapeutic drug monitoring in solid organ transplantation. Ther Drug Monit. 2009 Aug;31(4):416-35. doi: 10.1097/FTD.0b013e3181aa36cd. Review.
Zhou SF, Di YM, Chan E, Du YM, Chow VD, Xue CC, Lai X, Wang JC, Li CG, Tian M, Duan W. Clinical pharmacogenetics and potential application in personalized medicine. Curr Drug Metab. 2008 Oct;9(8):738-84. Review.
Rosso Felipe C, de Sandes TV, Sampaio EL, Park SI, Silva HT Jr, Medina Pestana JO. Clinical impact of polymorphisms of transport proteins and enzymes involved in the metabolism of immunosuppressive drugs. Transplant Proc. 2009 Jun;41(5):1441-55. doi: 10.1016/j.transproceed.2009.03.024. Review.
Claeys T, Van Dyck M, Van Damme-Lombaerts R. Pharmacokinetics of tacrolimus in stable paediatric renal transplant recipients. Pediatr Nephrol. 2010 Feb;25(2):335-42. doi: 10.1007/s00467-009-1331-6. Epub 2009 Nov 3.
Montini G, Ujka F, Varagnolo C, Ghio L, Ginevri F, Murer L, Thafam BS, Carasi C, Zacchello G, Plebani M. The pharmacokinetics and immunosuppressive response of tacrolimus in paediatric renal transplant recipients. Pediatr Nephrol. 2006 May;21(5):719-24. Epub 2006 Mar 21.
Naesens M, Salvatierra O, Li L, Kambham N, Concepcion W, Sarwal M. Maturation of dose-corrected tacrolimus predose trough levels in pediatric kidney allograft recipients. Transplantation. 2008 Apr 27;85(8):1139-45. doi: 10.1097/TP.0b013e31816b431a.
Ferraris JR, Argibay PF, Costa L, Jimenez G, Coccia PA, Ghezzi LF, Ferraris V, Belloso WH, Redal MA, Larriba JM. Influence of CYP3A5 polymorphism on tacrolimus maintenance doses and serum levels after renal transplantation: age dependency and pharmacological interaction with steroids. Pediatr Transplant. 2011 Aug;15(5):525-32. doi: 10.1111/j.1399-3046.2011.01513.x. Epub 2011 Jun 28.
Fakhoury M, Litalien C, Medard Y, Cavé H, Ezzahir N, Peuchmaur M, Jacqz-Aigrain E. Localization and mRNA expression of CYP3A and P-glycoprotein in human duodenum as a function of age. Drug Metab Dispos. 2005 Nov;33(11):1603-7. Epub 2005 Jul 27.
Kanamori M, Takahashi H, Echizen H. Developmental changes in the liver weight- and body weight-normalized clearance of theophylline, phenytoin and cyclosporine in children. Int J Clin Pharmacol Ther. 2002 Nov;40(11):485-92.
Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology--drug disposition, action, and therapy in infants and children. N Engl J Med. 2003 Sep 18;349(12):1157-67. Review.
Bartelink IH, Rademaker CM, Schobben AF, van den Anker JN. Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations. Clin Pharmacokinet. 2006;45(11):1077-97. Review.

Responsible Party: Noël Knops, Dr, Universitaire Ziekenhuizen Leuven
ClinicalTrials.gov Identifier: NCT01767350     History of Changes
Other Study ID Numbers: S55088
First Submitted: January 10, 2013
First Posted: January 14, 2013
Last Update Posted: December 15, 2015
Last Verified: December 2015

Keywords provided by Noël Knops, Universitaire Ziekenhuizen Leuven:
Pediatric transplantation
Pharmacogenetics
Pharmacokinetics
Calcineurin inhibitors
CYP3A
Pgp

Additional relevant MeSH terms:
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs


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