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Abstract

Introduction

Intrapatient variability (IPV) of tacrolimus and its predictors post-lung transplant are unclear.

Project Aims

This program evaluation aimed to characterize the IPV of immediate-release versus LCP-tacrolimus and predictors of variability ≥30% in lung transplant recipients.

Design

Adult lung transplant recipients who received immediate-release- or LCP-tacrolimus from January 2016 through August 2023 were included in this single-center retrospective evaluation. Immediate-release- and LCP-tacrolimus groups were matched 2:1 by time from transplant, presence of azole antifungal, and ethnicity. Three previously published equations calculated IPV. Outcomes to determine clinical impact of tacrolimus variability included de novo donor-specific antibody (DSA) development, rejection, graft loss/mortality, eGFR <60 mL/min, infection. Time in therapeutic range was assessed. Data were analyzed to determine predictors of variability ≥30%.

Results

There were no significant differences in the variability of immediate-release- versus LCP-tacrolimus among 3 equations used. There was no difference in de novo DSA development, rejection, graft loss, mortality, eGFR <60 mL/min, or infection between groups. Recipients with rejection during follow-up had higher variability compared to those who did not (P = .04). Presence of CYP34A inhibition predicted variability >30% in multivariate analysis. Immediate-release tacrolimus had higher time in therapeutic range versus LCP-tacrolimus, 67% versus 33%, (P = .15).

Conclusion

The IPV and associated clinical outcomes of immediate-release versus LCP-tacrolimus in lung transplant recipients did not significantly differ. Development of acute cellular rejection within 1 year follow-up was associated with higher tacrolimus variability regardless of formulation.

Keywords

clinical outcomes rejection outcomes pharmacology pharmacokinetics research quantitative methods descriptive comparative statistics descriptive infection

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References

Kandaswamy

Stock

Miller

, et al. OPTN/SRTR 2021 annual data report: pancreas. Am J Transplant. 2023;23(2 Suppl 1):S121-S177. doi:https://doi.org/10.1016/j.ajt.2023.02.005

Valapour

Lehr

Schladt

, et al. OPTN/SRTR 2021 annual data report: Lung. Am J Transplant. 2023;23(2 Suppl 1):S379-S442. doi:https://doi.org/10.1016/j.ajt.2023.02.009

Kwong

Ebel

Kim

, et al. OPTN/SRTR 2021 annual data report: Liver. Am J Transplant. 2023;23(2 Suppl 1):S178-S263. doi:https://doi.org/10.1016/j.ajt.2023.02.006

Lentine

Smith

Miller

, et al. OPTN/SRTR 2021 annual data report: Kidney. Am J Transplant. 2023;23(2 Suppl 1):S21-S120. doi:https://doi.org/10.1016/j.ajt.2023.02.004

Horslen

Wood

Cafarella

Schnellinger

. OPTN/SRTR 2021 annual data report: Intestine. Am J Transplant. 2023;23(2 Suppl 1):S264-S299. doi:https://doi.org/10.1016/j.ajt.2023.02.007

Colvin

Smith

Ahn

, et al. OPTN/SRTR 2021 annual data report: Heart. Am J Transplant. 2023;23(2 Suppl 1):S300-S378. doi:https://doi.org/10.1016/j.ajt.2023.02.008

Venkataramanan

Swaminathan

Prasad

, et al. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet. 1995;29(6):404-430. doi:https://doi.org/10.2165/00003088-199529060-00003

Liu

Zhang

Ming

. Pharmacokinetics, pharmacodynamics and pharmacogenetics of tacrolimus in kidney transplantation. Curr Drug Metab. 2018;19(6):513-522. doi:https://doi.org/10.2174/1389200219666180129151948

Langone

Steinberg

Gedaly

, et al. Switching STudy of kidney TRansplant PAtients with tremor to LCP-TacrO (STRATO): An open-label, multicenter, prospective phase 3b study. Clin Transplant. 2015;29(9):796-805. doi:https://doi.org/10.1111/ctr.12581

10.

Tremblay

Nigro

Weinberg

Woodle

Alloway

. A steady-state head-to-head pharmacokinetic comparison of all FK-506 (tacrolimus) formulations (ASTCOFF): An open-label, prospective, randomized, two-arm, three-period crossover study. A J Transplant. 2017;17(2):432-442. doi:https://doi.org/10.1111/ajt.13935

11.

Franco

Más-Serrano

Balibrea

, et al. Envarsus, a novelty for transplant nephrologists: Observational retrospective study. Nefrologia (Engl Ed). 2019;39(5):506-512. doi:https://doi.org/10.1016/j.nefro.2018.11.009

12.

Shuker

van Gelder

Hesselink

. Intra-patient variability in tacrolimus exposure: Causes, consequences for clinical management. Transplant Rev (Orlando). 2015;29(2):78-84. doi: https://doi.org/10.1016/j.trre.2015.01.002

13.

Trofe-Clark

Brennan

West-Thielke

, et al. Results of ASERTAA, a randomized prospective crossover pharmacogenetic study of immediate-release versus extended-release tacrolimus in African American kidney transplant recipients. Am J Kidney Dis. 2018;71(3):315-326. doi:https://doi.org/10.1053/j.ajkd.2017.07.018

14.

Süsal

Döhler

. Late intra-patient tacrolimus trough level variability as a major problem in kidney transplantation: A collaborative transplant study report. Am J Transplant. 2019;19(10):2805-2813. doi:https://doi.org/10.1111/ajt.15346

15.

Coste

Lemaitre

. The role of intra-patient variability of tacrolimus drug concentrations in solid organ transplantation: A focus on liver, heart, lung and pancreas. Pharmaceutics. 2022;14(2):379. doi:https://doi.org/10.3390/pharmaceutics14020379

16.

Whalen

Glen

Harkins

, et al. High intrapatient tacrolimus variability is associated with worse outcomes in renal transplantation using a low-dose tacrolimus immunosuppressive regime. Transplantation. 2017;101(2):430-436. doi:https://doi.org/10.1097/tp.0000000000001129

17.

Miller

Jane

, Allan

Madsen

. Novel approaches for long-term lung transplant survival. Front Immunol. 2022;13:931251. doi:https://doi.org/10.3389/fimmu.2022.931251

18.

Evans

Beermann

Lee

, et al. Impact of tacrolimus trough variability on acute rejection following lung transplantation. Transplant Proc. 2022;54(8):2270-2276. doi:https://doi.org/10.1016/j.transproceed.2022.08.007

19.

Borra

LCP

Roodnat

Kal

Mathot

Weimar

van Gelder

. High within-patient variability in the clearance of tacrolimus is a risk factor for poor long-term outcome after kidney transplantation. Nephrol Dial Transplant. 2010;25(8):2757-2763. doi:https://doi.org/10.1093/ndt/gfq096

20.

Bunthof

KLW

Al-Hassany

Nakshbandi

, et al. A randomized crossover study comparing different tacrolimus formulations to reduce intrapatient variability in tacrolimus exposure in kidney transplant recipients. Clin Transl Sci. 2022;15(4):930-941. doi:https://doi.org/10.1111/cts.13206

21.

Del Bello

Congy-Jolivet

Danjoux

, et al. High tacrolimus intra-patient variability is associated with graft rejection, and de novo donor-specific antibodies occurrence after liver transplantation. World J Gastroenterol. 2018;24(16):1795-1802.

22.

Husain

Camargo

. Invasive aspergillosis in solid-organ transplant recipients: Guidelines from the American society of transplantation infectious diseases community of practice. Clin Transplant. 2019;33(9):e13544. doi:https://doi.org/10.1111/ctr.13544

Comparison of Intrapatient Variability of IR-Tacrolimus Versus LCP-Tacrolimus in a Cohort of Lung Transplant Recipients

Abstract

Introduction

Project Aims

Design

Results

Conclusion

Keywords

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References