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Abstract: TH-PO359

Association Between CYP3A5 SNP rs776746 and Tacrolimus Dose: Single Transplant Center Experience in Southern Chile

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Navarro, Gustavo Alonso, Universidad Austral de Chile, Valdivia, Chile
  • Carmona, Rodolfo, Universidad Austral de Chile, Valdivia, Chile
  • Leiva Gonzalez, Marina, Hospital Intercultural de Nueva Imperial, Temuco, Temuco, Chile
  • Plaza, Anita, Universidad Austral de Chile, Valdivia, Chile
  • Muñoz, Daniel, Hospital Base Valdivia, Valdivia, Chile
  • Ardiles, Leopoldo G., Universidad Austral de Chile, Valdivia, Chile
  • Verdugo, Ricardo A., Universidad de Chile, Santiago, Chile
  • Mezzano, Sergio A., Universidad Austral de Chile, Valdivia, Chile
  • Krall, Paola, Universidad Austral de Chile, Valdivia, Chile
  • Flores, Claudio, Universidad Austral de Chile, Valdivia, Chile
Background

Tacrolimus (TAC) is a common immunosuppresor used in renal transplant (RTx) that requires monitoring to minimize risks. The best marker of TAC exposition is 24 hrs-AUC, but only Co is typically monitored. TAC is metabolized by CYP3A5 that contains a SNP (rs776746 A>G) associated in worldwide cohorts to slow (GG), intermediate (AG) or rapid (AA) TAC metabolism. The aim of this study was 1) to determine the association between rs776746 and TAC doses, 2) to establish if Co had a good correlation with AUC, 3) to analyze the genotype frequencies in Chile and their relationship with the Mapuche (Native Amerindian) ancestry.

Methods

A retrospective study was performed in 57 RTx adults of a single center using TAC of prolonged liberation for more than 3 months. The SNP rs776746 was analyzed by PCR Taqman/sequencing. AUC was determined in 16 patients with the three genotypes (GG/AG/AA). Mapuche ancestry in association to the genotypes was analyzed with the DNA repository in ChileGenómico.

Results

The mean age of the patients was 43 yrs [17-71 yrs], 51% female, 81% RTx with cadaveric donor, median time of RTx was 2.7 yrs. At the time of recruitment, 60% presented C0 between 5-10 ng/ml. We identified 58%, 26% and 16% of subjects with the GG, AG or AA genotype, respectively. The dose/weight (mg/kg) resulted GG=0.06±0.03, AG=0.12±0.05 and AA=0.15±0.05 (mg/kg) that were statistically different between GG-AA and GG-AG (p<0.001). The highest correlation between Cx and AUC was C12 (r=0.97) and C0 (r=0.96), independently of the genotype. The Mapuche ancestry percentage resulted 26% 30% and 37% for GG, AG and AA, respectively (p<0.0001).

Conclusion

A high prevalence of the GG genotype was identified, associated to lower requirements of TAC doses, but carriers of at least one A allele duplicated TAC dose. Chilean population has a mixed genetic ancestry and Mapuche ancestry appears to be associated with higher TAC doses, because of higher A allele frequency. Co turns to be an optimal marker of drug exposition. Our results demonstrate the potential clinical value of the CYP3A5 genotype to personalize therapy in Chile, to facilitate post-RTx monitoring, as well as improve credibility of patients TAC adherence. Grants FONDECYT 111-40242, FONDECYT 116-0465.

Funding

  • Government Support - Non-U.S.