Determinants of Immunosuppressive Dose Requirements in Children After Solid Organ Transplantation
NCT ID: NCT01767350
Last Updated: 2015-12-15
Study Results
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Basic Information
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COMPLETED
60 participants
OBSERVATIONAL
2013-02-28
2015-01-31
Brief Summary
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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
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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.
Conditions
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Keywords
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Study Design
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COHORT
RETROSPECTIVE
Study Groups
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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
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.
Interventions
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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 Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Extensive pharmacokinetic study of immunosuppression (AUC) performed during follow up
* Consent of child/caretaker
Exclusion Criteria
1 Year
30 Years
ALL
No
Sponsors
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Universitaire Ziekenhuizen KU Leuven
OTHER
Responsible Party
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Noël Knops
Dr
Principal Investigators
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Noel Knops, MD
Role: PRINCIPAL_INVESTIGATOR
Universitaire Ziekenhuizen KU Leuven
Locations
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University Hospitals Leuven
Leuven, , Belgium
Countries
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References
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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, 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.
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.
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.
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.
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.
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.
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.
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.
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. doi: 10.1007/s00467-006-0014-9. 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, 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.
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.
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.
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.
Other Identifiers
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S55088
Identifier Type: -
Identifier Source: org_study_id