Impact of IL-6 and IL-10 genotypes on tacrolimus dose requirements in kidney transplant recipients: Monte Carlo analysis

Abstract

Introduction: IL-6 and IL-10 may affect the activity of cytochrome P450 (CYP) 3A enzymes involved in tacrolimus (Tac) metabolism. Moreover, the effect of IL-6 and IL-10 on Tac pharmacokinetics may differ with respect to the genetic variations in their genes. Aim: To examine the influence of IL-6 and IL-10 gene polymorphisms on Tac dose requirements and exposure over a 5-year period following kidney transplantation. Univariate and standard multivariate linear regression and Monte Carlo analysis were performed to investigate potential covariates influencing Tac dose-adjusted trough concentration (C₀/D) in various post-transplantation periods. Materials & methods: IL-6 (-174G > C), IL-10 (-1082G > A, -819C > T and -592C > A) genotype, Tac daily dose, C₀, C₀/D and intrapatient variability data were collected from 113 patients. Results: Multivariate regression analysis and accompanied Monte Carlo simulation underscore the importance of considering IL-6 -174G > C and IL-10 -1082G > A gene polymorphisms, alongside Tac metabolic phenotype and post-transplantation period, when tailoring Tac dosage regimen. Conclusion: This study provides valuable insights regarding the individualized adjustment of Tac treatment in various post-transplantation periods.

Article highlights

• Inter-individual variability in Tac exposure can be explained to a considerable extent by Tac metabolism rate or phenotype. In addition, it was assumed that interleukin gene polymorphisms may account for a portion of the residual variability.

• Patients in the present study were classified into three groups based on the Tac metabolic phenotype: <1.05 ng/ml/mg (FM), 1.05–1.54 ng/ml/mg (IM) and ≥1.55 ng/ml/mg (SM), and it was demonstrated that Tac metabolic phenotype significantly and independently affected Tac exposure.

• Concerning the IL-6 -174G > C polymorphism, the carriers of the -174GG genotype exhibit higher Tac dose requirements (expressed as Tac C₀/D) compared to the carriers of the IL-6 -174C allele during the entire observation period of five years post-transplantation.

• Regarding the IL-10 polymorphisms, it was found that IL-10 -1082G > A polymorphism was associated with Tac pharmacokinetics (predominantly in later post-transplantation periods), while such an association was not demonstrated for the IL-10 -819C > T or IL-10 -592C > A polymorphism (both polymorphisms were in complete linkage disequilibrium).

• The interleukin gene polymorphisms did not correlate with the Tac IPV.

• The significant predictors in multivariate regression analysis, in other words, Tac metabolic phenotype, IL-6 -174G > C polymorphisms, IL-10 -1082G > A polymorphism and period after transplantation, accounted for 35.8% of the Tac C₀/D variance.

• Using the MC simulation approach, the present study showed that fast metabolizers carrying IL-6 GG + IL-10 A genotype combination tended to have the lowest predicted Tac C₀/D values, while slow metabolizers with the IL-6 C + IL-10 GG genotype combination exhibited the highest predicted Tac C₀/D values.

• The assessment of the combined effect of the metabolic phenotype and interleukin gene polymorphisms on Tac exposure could potentially facilitate optimizing Tac dosage regimen.

Keywords: :

• gene polymorphism
• interleukin-10
• interleukin-6
• kidney transplantation
• tacrolimus

Supplemental material

Supplemental data for this article can be accessed at https://doi.org/10.1080/14622416.2024.2379227

Acknowledgments

The authors would like to thank the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grant No: 451-03-65/2024-03/200113) for financial support.

Author contributions

Conceptualization: N Stefanović and K Danković; methodology: N Stefanović, S Vujić, T Jevtović-Stoimenov; software: N Stefanović and I Pavlović; investigation: N Stefanović, K Danković and B Mitić; writing-review and editing: N Stefanović, K Danković and S Vujić; supervision: N Stefanović, R Veliĉković-Radovanović, B Mitić and T Cvetković; funding acquisition: T Cvetković and T Jevtović-Stoimenov. All authors have read and agreed to the published version of the manuscript.

Financial disclosure

This work was supported by a grant from the Ministry of Education, Science and Technological Development of the Republic of Serbia (grant No: 451-03-65/2024-03/200113). The authors have no other 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 apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity 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.

Writing disclosure

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

Ethical conduct of research

The authors state that they have obtained institutional review board approval from the Ethics Committee of the Faculty of Medicine, University of Nis (No 12-6972-2/5 from 07 February 2018. and No 12-3588-2/2 from 07 April 2022.) for the research described. In addition, the written informed consent was obtained from all patients for the inclusion of their medical and treatment history within this work.

Data availability statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions.

Additional information

Funding

This work was supported by a grant from the Ministry of Education, Science and Technological Development of the Republic of Serbia (grant No: 451-03-65/2024-03/200113).