Effect of CYP3A5 on the Once-Daily Tacrolimus Conversion in Stable Liver Transplant Patients

Jong Man Kim, Je Ho Ryu, Kwang-Woong Lee, Suk Kyun Hong, Kwangho Yang, Gyu-Seong Choi, Young-Ae Kim, Ju-Yeun Lee, Nam-Joon Yi, Choon Hyuck David Kwon, Chong Woo Chu, Kyung-Suk Suh, Jae-Won Joh, Jong Man Kim, Je Ho Ryu, Kwang-Woong Lee, Suk Kyun Hong, Kwangho Yang, Gyu-Seong Choi, Young-Ae Kim, Ju-Yeun Lee, Nam-Joon Yi, Choon Hyuck David Kwon, Chong Woo Chu, Kyung-Suk Suh, Jae-Won Joh

Abstract

Cytochrome P450 (CYP) 3A5 polymorphism influences tacrolimus metabolism, but its effect on the drug pharmacokinetics in liver transplant recipients switched to once-daily extended-release formulation remains unknown. The aim of this study is to analyze the effect of CYP3A5 polymorphism on liver function after once-daily tacrolimus conversion in liver transplant patients. A prospective open-label study included 60 stable liver transplant recipients who underwent 1:1 conversion from twice-daily tacrolimus to once-daily tacrolimus. All participants were genotyped for CYP3A5 polymorphism. The study was registered at ClinicalTrials.gov (NCT02882113). Twenty-eight patients were enrolled in the CYP3A5 expressor group and 32 in the non-expressor group. Although there was no statistical difference, incidence of liver dysfunction was higher in the expressor group than in the non-expressor group when converted to once-daily extended-release tacrolimus (p = 0.088). No biopsy-proven acute rejection, graft failure, and mortality were observed in either group. The decrease in dose-adjusted trough level (-42.9% vs. -26.1%) and dose/kg-adjusted trough level of tacrolimus (-40.0% vs. -23.7%) was significantly greater in the expressor group than in the non-expressors after the conversion. A pharmacokinetic analysis was performed in 10 patients and tacrolimus absorption in the non-expressor group was slower than in the expressor group. In line with this observation, the area under the curve for once-daily tacrolimus correlated with trough level (Cmin) in the non-expressors and peak concentration (Cmax) in the expressors. CYP3A5 genotyping in liver transplant recipients leads to prediction of pharmacokinetics after switching from a twice-daily regimen to a once-daily dosage form, which makes it possible to establish an appropriate dose of tacrolimus.

Keywords: immunosuppression; pharmacokinetics; tacrolimus.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Study population. FAS, full analysis set; PP, per-protocol set.
Figure 2
Figure 2
Laboratory parameters of CYP3A5 expressors and non-expressors determined during regular control visits in per-protocol set (medians with 95% confidence interval). (A) Aspartate aminotransferase (AST), (B) Alanine aminotransferase (ALT), (C) total bilirubin, (D) Alkaline phosphatase (ALP), and (E) eGFR.
Figure 3
Figure 3
Tacrolimus exposure in CYP3A5 expressors and non-expressors determined during regular control visits in per-protocol set (medians with 95% confidence interval). (A) trough level of tacrolimus, (B) daily tacrolimus dose, (C) tacrolimus dose/weight, (D) dose-adjusted C0, and (E) dose/kg-adjusted C0.
Figure 4
Figure 4
(A) 24-h arithmetic mean whole blood tacrolimus concentrations (ng/mL) and standard deviation for the twice-daily and once-daily formulations; (B) Correlation between the area under the curve (AUC) and Cmin or Cmax in the expressor group after conversion to once-daily extended-release tacrolimus; (C) Correlation between the area under the curve (AUC) and Cmin or Cmax in the non-expressor group after conversion to once-daily extended-release tacrolimus.
Figure 5
Figure 5
Adverse event profiles in the expressors and non-expressors (Full Analysis Set) after conversion from twice-daily to once-daily extended-release tacrolimus.

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Source: PubMed

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