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Influence of CYP3A5 polymorphism on tacrolimus drug dosing in Indian renal allograft recipients: initial experience
Molecular Cytogenetics volume 7, Article number: P98 (2014)
Tacrolimus (Tac) is the mainstay of standard immunosuppressive regime in renal transplantation today. However, it needs regular drug level monitoring in view of narrow therapeutic window to keep blood level in therapeutic range. The objective of the study was to assess the potential influence of a functional polymorphism in CYP3A5*3 gene on dose requirements and trough blood levels of tacrolimus in renal transplant patients
Materials & methods
This prospective observational study included 20 patients of end stage renal disease who underwent renal transplantion and a follow up of 1 year at our hospital. All the patients were started on standard immunosuppressive regime of Tacrolimus-Mycophenolate mofetil along with steroids with a starting dose of Tac 0.08 mg/kg/day. Genotype of CYP3A5 was studied in 20 patients requiring low dose of Tac. At 7th and 30th day, and 3 monthly after transplant, Tac dosages (mg/kg/d), were adjusted based on blood levels and complications. Polymerase chain reaction, followed by restriction fragment length polymorphism analysis was used for genotyping CYP3A5*3 gene (A6986G) in intron 3.
Out of 20 patients (17 males and 3 females) included in the study, 16 had live related renal transplantation and 4 had diseased donor renal transplantation. Out of 20 patients 16 were found to have CYP3A5 homozygous status (A3986G polymorphism in CYP3A5*3 gene-wild allele) and 4 with heterozygous status. Patients of CYP3A5 homozygous status had mean Tac level of 16.84 ng/dL, median of 15.5 ng/dL (range- 13.2-25 ng/dL) on 7th day of transplant. So Tac dose was reduced to achieve TDL and mean Tac level at 30th day of transplant was 6.6 ng/dL and median of 7.4 ng/dL (range- 5.5-12.5 ng/dL). At 6th month and 12th month of transplant, mean Tac levels were 6.1 ng/dL and 5.9 ng/dL. In patients having CYP3A5 homozygous status, mean and median Tac dose after 4 weeks was 0.03 mg/kg/day (range- 0.008 to 0.05 mg/kg/day) and mean creatinine was 1.17 mg/dL (range-0.8 to 1.4 mg/dL) after 30th day. Remaining 4 patients having CYP3A5 heterozygous status were maintaining TDL at Tac dose of 0.06 mg/kg/day. Five patients had graft biopsy during first 4 weeks of renal transplant showing acute tubular necrosis (ATN) in three patients, acute cellular rejection in one patient and cellular rejection with evidence of calcineurine inhibitor (CNI) toxicity in one patient.
This study demonstrates the usefulness of CYP3A5 genotype in transplant patients taking Tacrolimus-Mycophenolate mofetil and also shows that majority of our patients carry mutant allele A3986G in CYP3A5*3 gene.
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Patel, M., Gumber, M., Kute, V. et al. Influence of CYP3A5 polymorphism on tacrolimus drug dosing in Indian renal allograft recipients: initial experience. Mol Cytogenet 7 (Suppl 1), P98 (2014). https://doi.org/10.1186/1755-8166-7-S1-P98
- Acute Tubular Necrosis
- Restriction Fragment Length Polymorphism Analysis
- A3986G Polymorphism
- Acute Cellular Rejection