A randomized crossover study comparing different tacrolimus formulations to reduce intrapatient variability in tacrolimus exposure in kidney transplant recipients

Kim L.W. Bunthof; Linda Al-Hassany; Gizal Nakshbandi; Dennis A. Hesselink; Ron H.N. van Schaik; Marc A.G.J. ten Dam; Marije C. Baas; Luuk B. Hilbrands; Teun van Gelder

doi:10.1111/cts.13206

A randomized crossover study comparing different tacrolimus formulations to reduce intrapatient variability in tacrolimus exposure in kidney transplant recipients

Kim L.W. Bunthof^*
, Linda Al-Hassany
, Gizal Nakshbandi
, Dennis A. Hesselink
, Ron H.N. van Schaik
, Marc A.G.J. ten Dam
, Marije C. Baas
, Luuk B. Hilbrands
, Teun van Gelder

^*Corresponding author for this work

Canisius Wilhelmina Hospital
Radboud University Medical Center

Research output: Contribution to journal › Article › Academic › peer-review

15 Citations (Scopus)

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Abstract

A high intrapatient variability (IPV) in tacrolimus exposure is a risk factor for poor long-term outcomes after kidney transplantation. The main objective of this trial was to investigate whether tacrolimus IPV decreases after switching patients from immediate-release (IR)-tacrolimus to either extended-release (ER)-tacrolimus or LifeCyclePharma (LCP)-tacrolimus. In this randomized, prospective, open-label, cross-over trial, adult kidney transplant recipients on a stable immunosuppressive regimen, including IR-tacrolimus, were randomized for conversion to ER-tacrolimus or LCP-tacrolimus, and for the order in which IR-tacrolimus and the once-daily formulations were taken. Patients were followed 6 months for each formulation, with monthly tacrolimus predose concentration assessments to calculate the IPV. The IPV was defined as the coefficient of variation (%) of dose corrected predose concentrations. Ninety-two patients were included for analysis of the primary outcome. No significant differences between the IPV of IR-tacrolimus (16.6%) and the combined once-daily formulations (18.3%) were observed (% difference +1.7%, 95% confidence interval [CI] −1.1% to ‒4.5%, p = 0.24). The IPV of LCP-tacrolimus (20.1%) was not significantly different from the IPV of ER-tacrolimus (16.5%, % difference +3.6%, 95% CI −0.1% to 7.3%, p = 0.06). In conclusion, the IPV did not decrease after switching from IR-tacrolimus to either ER-tacrolimus or LCP-tacrolimus. These results provide no arguments to switch kidney transplant recipients from twice-daily (IR) tacrolimus formulations to once-daily (modified-release) tacrolimus formulations when the aim is to lower the IPV.

Original language	English
Pages (from-to)	930-941
Number of pages	12
Journal	Clinical and Translational Science
Volume	15
Issue number	4
DOIs	https://doi.org/10.1111/cts.13206
Publication status	Published - Apr 2022

Bibliographical note

Funding Information:
This study was supported by Chiesi Pharmaceuticals B.V. The Netherlands, as local representative of the marketing authorization holder Chiesi Farmaceutici S.p.A. of LCPT (Envarsus). The underlying study represents an investigator‐initiated trial. The study was designed by the authors alone without any external input regarding design, analysis, or approval for the manuscript either by Chiesi Pharmaceuticals B.V. The Netherlands or by any other unmentioned party. The authors themselves did not receive any financial support with regard to this study. D.A.H. has received lecture fees and consulting fees from Astellas Pharma, Chiesi Pharma, Medincell, Novartis Pharma, and Vifor Pharma. He has received grant support from Astellas Pharma, Bristol‐Myers Squibb, and Chiesi Pharma (paid to his institution). D.A.H. does not have employment or stock ownership at any of these companies, and neither does he have patents or patent applications. L.B.H. has received lecture fees and consulting fees from Astellas, Chiesi, and Novartis. He has received grant support from Chiesi and Sandoz (paid to his institution). L.B.H. does not have employment or stock ownership at any of these companies, and neither does he have patents or patent applications. T.vG. has received lecture fees and study grants from Chiesi and Astellas, in addition to consulting fees from Roche Diagnostics, Thermo Fisher, Vitaeris, CSL Behring, Astellas, and Aurinia Pharma. In all cases, money has been transferred to hospital accounts, and none has been paid to his personal bank accounts. T.vG. does not have employment or stock ownership at any of these companies, and neither does he have patents or patent applications. All other authors declared no competing interests for this work.

Publisher Copyright: © 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

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Clinical Translational Sci - 2021 - Bunthof - A randomized crossover study comparing different tacrolimus formulations toFinal published version, 396 KBLicence: CC BY-NC-ND

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Bunthof, K. L. W., Al-Hassany, L., Nakshbandi, G., Hesselink, D. A., van Schaik, R. H. N., ten Dam, M. A. G. J., Baas, M. C., Hilbrands, L. B., & van Gelder, T. (2022). A randomized crossover study comparing different tacrolimus formulations to reduce intrapatient variability in tacrolimus exposure in kidney transplant recipients. Clinical and Translational Science, 15(4), 930-941. https://doi.org/10.1111/cts.13206

@article{2ff38fcb2e504835bf65a75ad71b2497,

title = "A randomized crossover study comparing different tacrolimus formulations to reduce intrapatient variability in tacrolimus exposure in kidney transplant recipients",

abstract = "A high intrapatient variability (IPV) in tacrolimus exposure is a risk factor for poor long-term outcomes after kidney transplantation. The main objective of this trial was to investigate whether tacrolimus IPV decreases after switching patients from immediate-release (IR)-tacrolimus to either extended-release (ER)-tacrolimus or LifeCyclePharma (LCP)-tacrolimus. In this randomized, prospective, open-label, cross-over trial, adult kidney transplant recipients on a stable immunosuppressive regimen, including IR-tacrolimus, were randomized for conversion to ER-tacrolimus or LCP-tacrolimus, and for the order in which IR-tacrolimus and the once-daily formulations were taken. Patients were followed 6 months for each formulation, with monthly tacrolimus predose concentration assessments to calculate the IPV. The IPV was defined as the coefficient of variation (\%) of dose corrected predose concentrations. Ninety-two patients were included for analysis of the primary outcome. No significant differences between the IPV of IR-tacrolimus (16.6\%) and the combined once-daily formulations (18.3\%) were observed (\% difference +1.7\%, 95\% confidence interval [CI] −1.1\% to ‒4.5\%, p = 0.24). The IPV of LCP-tacrolimus (20.1\%) was not significantly different from the IPV of ER-tacrolimus (16.5\%, \% difference +3.6\%, 95\% CI −0.1\% to 7.3\%, p = 0.06). In conclusion, the IPV did not decrease after switching from IR-tacrolimus to either ER-tacrolimus or LCP-tacrolimus. These results provide no arguments to switch kidney transplant recipients from twice-daily (IR) tacrolimus formulations to once-daily (modified-release) tacrolimus formulations when the aim is to lower the IPV.",

author = "Bunthof, \{Kim L.W.\} and Linda Al-Hassany and Gizal Nakshbandi and Hesselink, \{Dennis A.\} and \{van Schaik\}, \{Ron H.N.\} and \{ten Dam\}, \{Marc A.G.J.\} and Baas, \{Marije C.\} and Hilbrands, \{Luuk B.\} and \{van Gelder\}, Teun",

note = "Funding Information: This study was supported by Chiesi Pharmaceuticals B.V. The Netherlands, as local representative of the marketing authorization holder Chiesi Farmaceutici S.p.A. of LCPT (Envarsus). The underlying study represents an investigator‐initiated trial. The study was designed by the authors alone without any external input regarding design, analysis, or approval for the manuscript either by Chiesi Pharmaceuticals B.V. The Netherlands or by any other unmentioned party. The authors themselves did not receive any financial support with regard to this study. D.A.H. has received lecture fees and consulting fees from Astellas Pharma, Chiesi Pharma, Medincell, Novartis Pharma, and Vifor Pharma. He has received grant support from Astellas Pharma, Bristol‐Myers Squibb, and Chiesi Pharma (paid to his institution). D.A.H. does not have employment or stock ownership at any of these companies, and neither does he have patents or patent applications. L.B.H. has received lecture fees and consulting fees from Astellas, Chiesi, and Novartis. He has received grant support from Chiesi and Sandoz (paid to his institution). L.B.H. does not have employment or stock ownership at any of these companies, and neither does he have patents or patent applications. T.vG. has received lecture fees and study grants from Chiesi and Astellas, in addition to consulting fees from Roche Diagnostics, Thermo Fisher, Vitaeris, CSL Behring, Astellas, and Aurinia Pharma. In all cases, money has been transferred to hospital accounts, and none has been paid to his personal bank accounts. T.vG. does not have employment or stock ownership at any of these companies, and neither does he have patents or patent applications. All other authors declared no competing interests for this work. Publisher Copyright: {\textcopyright} 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.",

year = "2022",

month = apr,

doi = "10.1111/cts.13206",

language = "English",

volume = "15",

pages = "930--941",

journal = "Clinical and Translational Science",

issn = "1752-8054",

publisher = "John Wiley \& Sons Inc.",

number = "4",

}

Bunthof, KLW, Al-Hassany, L , Nakshbandi, G , Hesselink, DA , van Schaik, RHN, ten Dam, MAGJ, Baas, MC, Hilbrands, LB & van Gelder, T 2022, 'A randomized crossover study comparing different tacrolimus formulations to reduce intrapatient variability in tacrolimus exposure in kidney transplant recipients', Clinical and Translational Science, vol. 15, no. 4, pp. 930-941. https://doi.org/10.1111/cts.13206

A randomized crossover study comparing different tacrolimus formulations to reduce intrapatient variability in tacrolimus exposure in kidney transplant recipients. / Bunthof, Kim L.W.; Al-Hassany, Linda ; Nakshbandi, Gizal et al.
In: Clinical and Translational Science, Vol. 15, No. 4, 04.2022, p. 930-941.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - A randomized crossover study comparing different tacrolimus formulations to reduce intrapatient variability in tacrolimus exposure in kidney transplant recipients

AU - Bunthof, Kim L.W.

AU - Al-Hassany, Linda

AU - Nakshbandi, Gizal

AU - Hesselink, Dennis A.

AU - van Schaik, Ron H.N.

AU - ten Dam, Marc A.G.J.

AU - Baas, Marije C.

AU - Hilbrands, Luuk B.

AU - van Gelder, Teun

N1 - Funding Information: This study was supported by Chiesi Pharmaceuticals B.V. The Netherlands, as local representative of the marketing authorization holder Chiesi Farmaceutici S.p.A. of LCPT (Envarsus). The underlying study represents an investigator‐initiated trial. The study was designed by the authors alone without any external input regarding design, analysis, or approval for the manuscript either by Chiesi Pharmaceuticals B.V. The Netherlands or by any other unmentioned party. The authors themselves did not receive any financial support with regard to this study. D.A.H. has received lecture fees and consulting fees from Astellas Pharma, Chiesi Pharma, Medincell, Novartis Pharma, and Vifor Pharma. He has received grant support from Astellas Pharma, Bristol‐Myers Squibb, and Chiesi Pharma (paid to his institution). D.A.H. does not have employment or stock ownership at any of these companies, and neither does he have patents or patent applications. L.B.H. has received lecture fees and consulting fees from Astellas, Chiesi, and Novartis. He has received grant support from Chiesi and Sandoz (paid to his institution). L.B.H. does not have employment or stock ownership at any of these companies, and neither does he have patents or patent applications. T.vG. has received lecture fees and study grants from Chiesi and Astellas, in addition to consulting fees from Roche Diagnostics, Thermo Fisher, Vitaeris, CSL Behring, Astellas, and Aurinia Pharma. In all cases, money has been transferred to hospital accounts, and none has been paid to his personal bank accounts. T.vG. does not have employment or stock ownership at any of these companies, and neither does he have patents or patent applications. All other authors declared no competing interests for this work. Publisher Copyright: © 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

PY - 2022/4

Y1 - 2022/4

N2 - A high intrapatient variability (IPV) in tacrolimus exposure is a risk factor for poor long-term outcomes after kidney transplantation. The main objective of this trial was to investigate whether tacrolimus IPV decreases after switching patients from immediate-release (IR)-tacrolimus to either extended-release (ER)-tacrolimus or LifeCyclePharma (LCP)-tacrolimus. In this randomized, prospective, open-label, cross-over trial, adult kidney transplant recipients on a stable immunosuppressive regimen, including IR-tacrolimus, were randomized for conversion to ER-tacrolimus or LCP-tacrolimus, and for the order in which IR-tacrolimus and the once-daily formulations were taken. Patients were followed 6 months for each formulation, with monthly tacrolimus predose concentration assessments to calculate the IPV. The IPV was defined as the coefficient of variation (%) of dose corrected predose concentrations. Ninety-two patients were included for analysis of the primary outcome. No significant differences between the IPV of IR-tacrolimus (16.6%) and the combined once-daily formulations (18.3%) were observed (% difference +1.7%, 95% confidence interval [CI] −1.1% to ‒4.5%, p = 0.24). The IPV of LCP-tacrolimus (20.1%) was not significantly different from the IPV of ER-tacrolimus (16.5%, % difference +3.6%, 95% CI −0.1% to 7.3%, p = 0.06). In conclusion, the IPV did not decrease after switching from IR-tacrolimus to either ER-tacrolimus or LCP-tacrolimus. These results provide no arguments to switch kidney transplant recipients from twice-daily (IR) tacrolimus formulations to once-daily (modified-release) tacrolimus formulations when the aim is to lower the IPV.

AB - A high intrapatient variability (IPV) in tacrolimus exposure is a risk factor for poor long-term outcomes after kidney transplantation. The main objective of this trial was to investigate whether tacrolimus IPV decreases after switching patients from immediate-release (IR)-tacrolimus to either extended-release (ER)-tacrolimus or LifeCyclePharma (LCP)-tacrolimus. In this randomized, prospective, open-label, cross-over trial, adult kidney transplant recipients on a stable immunosuppressive regimen, including IR-tacrolimus, were randomized for conversion to ER-tacrolimus or LCP-tacrolimus, and for the order in which IR-tacrolimus and the once-daily formulations were taken. Patients were followed 6 months for each formulation, with monthly tacrolimus predose concentration assessments to calculate the IPV. The IPV was defined as the coefficient of variation (%) of dose corrected predose concentrations. Ninety-two patients were included for analysis of the primary outcome. No significant differences between the IPV of IR-tacrolimus (16.6%) and the combined once-daily formulations (18.3%) were observed (% difference +1.7%, 95% confidence interval [CI] −1.1% to ‒4.5%, p = 0.24). The IPV of LCP-tacrolimus (20.1%) was not significantly different from the IPV of ER-tacrolimus (16.5%, % difference +3.6%, 95% CI −0.1% to 7.3%, p = 0.06). In conclusion, the IPV did not decrease after switching from IR-tacrolimus to either ER-tacrolimus or LCP-tacrolimus. These results provide no arguments to switch kidney transplant recipients from twice-daily (IR) tacrolimus formulations to once-daily (modified-release) tacrolimus formulations when the aim is to lower the IPV.

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DO - 10.1111/cts.13206

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JO - Clinical and Translational Science

JF - Clinical and Translational Science

IS - 4

ER -

A randomized crossover study comparing different tacrolimus formulations to reduce intrapatient variability in tacrolimus exposure in kidney transplant recipients

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