Influence of Combined CYP3A4 and CYP3A5 Single-Nucleotide Polymorphisms on Tacrolimus Exposure in Kidney Transplant Recipients: A Study According to the Post-Transplant Phase

Abstract

Aim: The present study investigated in Tunisian renal transplant patients, genetic polymorphisms of CYP3A4 -392A>G and CYP3A5 6986A>G and their influence on tacrolimus (Tac) pharmacokinetics during early and late post-transplant (PT) phases and established customized ranges of Tac doses matching the C₀ target levels according to CYP3A4 and CYP3A5 genotype combination and the PT phase. Patients & methods: We included adult Tunisian patients having received Tac for de novo kidney grafts and undergone a therapeutic drug monitoring of Tac by morning C₀ monitoring during early (1 to 90 days) and late (over 90 days) PT phases. The genomic DNA was extracted from peripheral blood mononuclear cells using a salting-out procedure. CYP3A4 promoter (rs2740574; -392A>G) and CYP3A5 (rs776746; 6986A>G) SNP genotyping was analyzed using PCR-RFLP. Results: Fifty-two patients were enrolled in the study. During the early PT phase, the CYP3A5 polymorphism but not that of CYP3A4, correlates significantly with Tac dose-normalized C₀ (C₀/D ratio). During the late PT phase, the effect of CYP3A4 polymorphism becomes significant and that of CYP3A5 becomes nonsignificant on Tac C₀/D Tac. The mean daily doses (mg/kg) matching therapeutic C₀, regardless of the CYP3A genotypes, were 0.16 ± 0.05 and 0.10 ± 0.05 during early and late PT phase, respectively. Carriers of the CYP3A4*1B allele require higher doses to maintain the C₀ in the therapeutic range during the two PT phases. However, patients carrying the CYP3A5*1 require significant higher Tac doses, only during the early phase. Conclusion: Our data support a critical role of the CYP3A5 6986A>G and CYP3A4 -392A>G polymorphisms on the variation of Tac exposure during the early and the late PT phase, respectively. The establishment of customized Tac doses, according to CYP3A4/CYP3A5 genotype combination and the PT time, may allow preventing graft rejection and improving the safety profile of this drug. Further studies are needed to investigate this issue.

Keywords::

• CYP3A4
• CYP3A5
• post-transplant time
• southern Mediterranean
• tacrolimus
• TDM

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.