Impact of donor CYP3A5 genotype on pharmacokinetics of tacrolimus in South African paediatric liver transplant patients
Background. In the paediatric liver transplant programme in Johannesburg, South Africa (SA), tacrolimus is the calcineurin inhibitor of choice, comprising an essential component of the immunosuppression regimen. It is characterised by a narrow therapeutic index and wide interpatient variability...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
South African Medical Association
2024-04-01
|
| Series: | South African Medical Journal |
| Subjects: | |
| Online Access: | https://samajournals.co.za/index.php/samj/article/view/1367 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823860556805701632 |
|---|---|
| author | C Wheeler C Masimirembwa B Mthembu J Botha J Scholefield J Fabian |
| author_facet | C Wheeler C Masimirembwa B Mthembu J Botha J Scholefield J Fabian |
| author_sort | C Wheeler |
| collection | DOAJ |
| description |
Background. In the paediatric liver transplant programme in Johannesburg, South Africa (SA), tacrolimus is the calcineurin inhibitor of choice, comprising an essential component of the immunosuppression regimen. It is characterised by a narrow therapeutic index and wide interpatient variability, necessitating therapeutic drug monitoring of whole-blood concentrations. Pharmacogenetic research, although not representative of SA population groups, suggests that single-nucleotide polymorphisms within the cytochrome P450 3A5 (CYP3A5) gene contribute to the variability in tacrolimus dosing requirements. The rs776746 polymorphism, CYP3A5*3, results in a splice defect and a non-functional enzyme. Clinically, to reach the same tacrolimus concentration-to-dose ratio (CDR), expressors (CYP3A5*1/*1 and *1/*3) require a higher tacrolimus dose than non-expressors (*3/*3).
Objectives. To compare the pharmacokinetics of tacrolimus in paediatric liver transplant recipients with their donors’ CYP3A5 genotypes, considering both donor and recipient characteristics.
Methods. Blood samples from 46 living liver donors were collected, their genomic DNA was extracted, and their CYP3A5 genotype was established (polymerase chain reaction and restriction fragment length polymorphism analysis, validated by Sanger sequencing). The relationship of donor and recipient characteristics with the mean tacrolimus CDR was analysed using a general linear model. Non- confounding significant variables were included in a multiple regression model.
Results. The study showed that all expressor donors genotyped as CYP3A5*1/*1 were of black African self-reported race and ethnicity. During the first 15 days post-transplant, we found that children who received grafts from donor CYP3A5 expressors (CYP3A5*1/*1 and *1/*3) had significantly lower mean tacrolimus CDRs compared with those who received grafts from donor CYP3A5 non-expressors (*3/*3); the recipients of CYP3A5 expressor grafts therefore require higher doses of oral tacrolimus to achieve the same therapeutic target range. In addition, graft-to-recipient weight ratio and the CYP3A5 donor genotypes were independent factors that significantly (p<0.05) affected mean tacrolimus CDRs in recipients.
Conclusion. In this study, we showed that all CYP3A5*1 homozygote donors were of black African self-reported race and ethnicity, and tacrolimus CDRs in paediatric living-donor liver transplant recipients were significantly affected by donor graft size and donor CYP3A5 genotypes. Information from this study may inform the development of an Afrocentric tacrolimus precision-medicine algorithm to optimise recipient safety and graft outcomes.
|
| format | Article |
| id | doaj-art-308de063cec04406869cd396ff980e09 |
| institution | Kabale University |
| issn | 0256-9574 2078-5135 |
| language | English |
| publishDate | 2024-04-01 |
| publisher | South African Medical Association |
| record_format | Article |
| series | South African Medical Journal |
| spelling | doaj-art-308de063cec04406869cd396ff980e092025-02-10T12:26:12ZengSouth African Medical AssociationSouth African Medical Journal0256-95742078-51352024-04-011143b10.7196/SAMJ.2024.v114i3b.1367Impact of donor CYP3A5 genotype on pharmacokinetics of tacrolimus in South African paediatric liver transplant patientsC Wheeler0https://orcid.org/0000-0002-0604-3621C Masimirembwa1B Mthembu2J Botha3J Scholefield4J Fabian5Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South AfricaAfrican Institute of Biomedical Science and Technology, Harare, Zimbabwe. Sydney Brenner Institute of Molecular Bioscience (SBIMB), Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Sydney Brenner Institute of Molecular Bioscience (SBIMB), Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South AfricaTransplantation Services, Intermountain Medical Centre, Salt Lake City, Utah, USABioenegineering and Integrated Genomics Group, NextGen Health, Council for Scientific and Industrial Research, Pretoria, South AfricaWits Donald Gordon Medical Centre, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Parktown, Johannesburg, South Africa Background. In the paediatric liver transplant programme in Johannesburg, South Africa (SA), tacrolimus is the calcineurin inhibitor of choice, comprising an essential component of the immunosuppression regimen. It is characterised by a narrow therapeutic index and wide interpatient variability, necessitating therapeutic drug monitoring of whole-blood concentrations. Pharmacogenetic research, although not representative of SA population groups, suggests that single-nucleotide polymorphisms within the cytochrome P450 3A5 (CYP3A5) gene contribute to the variability in tacrolimus dosing requirements. The rs776746 polymorphism, CYP3A5*3, results in a splice defect and a non-functional enzyme. Clinically, to reach the same tacrolimus concentration-to-dose ratio (CDR), expressors (CYP3A5*1/*1 and *1/*3) require a higher tacrolimus dose than non-expressors (*3/*3). Objectives. To compare the pharmacokinetics of tacrolimus in paediatric liver transplant recipients with their donors’ CYP3A5 genotypes, considering both donor and recipient characteristics. Methods. Blood samples from 46 living liver donors were collected, their genomic DNA was extracted, and their CYP3A5 genotype was established (polymerase chain reaction and restriction fragment length polymorphism analysis, validated by Sanger sequencing). The relationship of donor and recipient characteristics with the mean tacrolimus CDR was analysed using a general linear model. Non- confounding significant variables were included in a multiple regression model. Results. The study showed that all expressor donors genotyped as CYP3A5*1/*1 were of black African self-reported race and ethnicity. During the first 15 days post-transplant, we found that children who received grafts from donor CYP3A5 expressors (CYP3A5*1/*1 and *1/*3) had significantly lower mean tacrolimus CDRs compared with those who received grafts from donor CYP3A5 non-expressors (*3/*3); the recipients of CYP3A5 expressor grafts therefore require higher doses of oral tacrolimus to achieve the same therapeutic target range. In addition, graft-to-recipient weight ratio and the CYP3A5 donor genotypes were independent factors that significantly (p<0.05) affected mean tacrolimus CDRs in recipients. Conclusion. In this study, we showed that all CYP3A5*1 homozygote donors were of black African self-reported race and ethnicity, and tacrolimus CDRs in paediatric living-donor liver transplant recipients were significantly affected by donor graft size and donor CYP3A5 genotypes. Information from this study may inform the development of an Afrocentric tacrolimus precision-medicine algorithm to optimise recipient safety and graft outcomes. https://samajournals.co.za/index.php/samj/article/view/1367TacrolimusCYP3A5PaediatricLiver TransplantLiving DonorPharmacogenetics |
| spellingShingle | C Wheeler C Masimirembwa B Mthembu J Botha J Scholefield J Fabian Impact of donor CYP3A5 genotype on pharmacokinetics of tacrolimus in South African paediatric liver transplant patients South African Medical Journal Tacrolimus CYP3A5 Paediatric Liver Transplant Living Donor Pharmacogenetics |
| title | Impact of donor CYP3A5 genotype on pharmacokinetics of tacrolimus in South African paediatric liver transplant patients |
| title_full | Impact of donor CYP3A5 genotype on pharmacokinetics of tacrolimus in South African paediatric liver transplant patients |
| title_fullStr | Impact of donor CYP3A5 genotype on pharmacokinetics of tacrolimus in South African paediatric liver transplant patients |
| title_full_unstemmed | Impact of donor CYP3A5 genotype on pharmacokinetics of tacrolimus in South African paediatric liver transplant patients |
| title_short | Impact of donor CYP3A5 genotype on pharmacokinetics of tacrolimus in South African paediatric liver transplant patients |
| title_sort | impact of donor cyp3a5 genotype on pharmacokinetics of tacrolimus in south african paediatric liver transplant patients |
| topic | Tacrolimus CYP3A5 Paediatric Liver Transplant Living Donor Pharmacogenetics |
| url | https://samajournals.co.za/index.php/samj/article/view/1367 |
| work_keys_str_mv | AT cwheeler impactofdonorcyp3a5genotypeonpharmacokineticsoftacrolimusinsouthafricanpaediatriclivertransplantpatients AT cmasimirembwa impactofdonorcyp3a5genotypeonpharmacokineticsoftacrolimusinsouthafricanpaediatriclivertransplantpatients AT bmthembu impactofdonorcyp3a5genotypeonpharmacokineticsoftacrolimusinsouthafricanpaediatriclivertransplantpatients AT jbotha impactofdonorcyp3a5genotypeonpharmacokineticsoftacrolimusinsouthafricanpaediatriclivertransplantpatients AT jscholefield impactofdonorcyp3a5genotypeonpharmacokineticsoftacrolimusinsouthafricanpaediatriclivertransplantpatients AT jfabian impactofdonorcyp3a5genotypeonpharmacokineticsoftacrolimusinsouthafricanpaediatriclivertransplantpatients |