Determinants of Immunosuppressive Dose Requirements in Children After Solid Organ Transplantation

Transplantation Infection Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01767350
• Other study ID #: S55088
• Status: Completed
• Phase: N/A
• First received: January 10, 2013
• Last updated: December 14, 2015
• Start date: February 2013
• Est. completion date: January 2015

Study information

• Verified date: December 2015
• Source: Universitaire Ziekenhuizen Leuven
• Contact: n/a
• Is FDA regulated: No
• Health authority: Belgium: Ethics Committee
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: January 2015
• Est. primary completion date: January 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year to 30 Years

Eligibility

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 Design

Observational Model: Cohort, Time Perspective: Retrospective

Related Conditions & MeSH terms

• Transplantation Infection

Intervention

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.

Locations

Country	Name	City	State
Belgium	University Hospitals Leuven	Leuven

Sponsors (1)

Lead Sponsor	Collaborator
Universitaire Ziekenhuizen Leuven

Country where clinical trial is conducted

Belgium, 

References & Publications (17)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Relative dose requirement of tacrolimus, ciclosporin or MMF	analysis of retrospective data concerning pharmacokinetic assessment as part of standard clinical care	1 yr	No
Secondary	Pharmacogenetic genotype	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	No