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, 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.