Determinants of Immunosuppressive Dose Requirements in Children After Solid Organ Transplantation

NCT01767350 | Completed

• 1 other identifier: S55088
• Study Type: observational
• Target: 60
• Locations: 1 country
• Sites: 1

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.

Conditions

Transplantation Infection

Keywords

Pediatric transplantation; Pharmacogenetics; Pharmacokinetics; Calcineurin inhibitors; CYP3A; Pgp

Outcome Measures

Primary Outcomes (1)

• Relative dose requirement of tacrolimus, ciclosporin or MMF

  analysis of retrospective data concerning pharmacokinetic assessment as part of standard clinical care

  1 yr

Secondary Outcomes (1)

• Pharmacogenetic genotype

  1 yr

Study Arms (1)

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

Interventions

Blood withdrawal for DNA PROCEDURE

Single withdrawal of 8 ml whole blood for DNA analysis, during a "standard" blood collection as part of standard clinical follow up.

Also known as: not applicalble

children with organ transplant

Eligibility Criteria

• Age: 1 Year - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

Pediatric recipients of a solid organ transplantation

You may qualify if:

• 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

Sponsors & Collaborators

• Universitaire Ziekenhuizen KU Leuven: lead

Study Sites (1)

University Hospitals Leuven

Leuven, 3000, Belgium

Location

Related Publications (17)

• 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.

  PMID: 21057388 BACKGROUND

• Opelz G, Susal C, Ruhenstroth A, Dohler 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.

  PMID: 20808265 BACKGROUND

• Opelz G, Dohler 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.

  PMID: 19300179 BACKGROUND

• 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.

  PMID: 20170205 BACKGROUND

• 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.

  PMID: 20214406 BACKGROUND

• 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.

  PMID: 18631854 BACKGROUND

• 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.

  PMID: 19536049 BACKGROUND

• 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. doi: 10.2174/138920008786049302.

  PMID: 18855611 BACKGROUND

• 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.

  PMID: 19545654 BACKGROUND

• 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.

  PMID: 19885684 BACKGROUND

• 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. doi: 10.1007/s00467-006-0014-9. Epub 2006 Mar 21.

  PMID: 16550361 BACKGROUND

• 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.

  PMID: 18431234 BACKGROUND

• 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.

  PMID: 21711429 BACKGROUND

• Fakhoury M, Litalien C, Medard Y, Cave 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. doi: 10.1124/dmd.105.005611. Epub 2005 Jul 27.

  PMID: 16049125 BACKGROUND

• 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. doi: 10.5414/cpp40485.

  PMID: 12698985 BACKGROUND

• 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. doi: 10.1056/NEJMra035092. No abstract available.

  PMID: 13679531 BACKGROUND

• 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. doi: 10.2165/00003088-200645110-00003.

  PMID: 17048973 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

tube of whole blood (8 ml) to be processed for DNA extraction and storage

MeSH Terms

Interventions

DNA

Intervention Hierarchy (Ancestors)

Nucleic Acids; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Noel Knops, MD

  Universitaire Ziekenhuizen KU Leuven

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr

Study Record Dates

• First Submitted: January 10, 2013
• First Posted: January 14, 2013
• Study Start: February 1, 2013
• Primary Completion: January 1, 2015
• Study Completion: January 1, 2015
• Last Updated: December 15, 2015

Record last verified: 2015-12

Locations

BE (1)