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, pp. 930–941

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.

Authors 9

1. Kim L. W. Bunthof corresponding

   Radboud University Nijmegen · Radboud University Medical Center · Bravis Ziekenhuis

   Affiliation as printed

   Department of Internal Medicine Bravis Hospital Roosendaal The Netherlands

   Department of Nephrology Radboud University Medical Center Nijmegen The Netherlands

   Department of Internal Medicine, Bravis Hospital, Roosendaal, The Netherlands

   Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands

2. Linda Al‐Hassany

   Erasmus MC

   Affiliation as printed

   Department of Hospital Pharmacy Erasmus University Medical Center Rotterdam The Netherlands

   Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands

3. Gizal Nakshbandi

   Erasmus MC

   Affiliation as printed

   Department of Hospital Pharmacy Erasmus University Medical Center Rotterdam The Netherlands

   Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands

4. Dennis Alexander Hesselink

   Erasmus MC · Erasmus MC Transplant Institute · Erasmus University Rotterdam

   Affiliation as printed

   Erasmus University Medical Center Erasmus MC Transplant Institute Rotterdam The Netherlands

   Internal Medicine Division of Nephrology and Transplantation Erasmus University Medical Center Rotterdam The Netherlands

   Erasmus University Medical Center, Erasmus MC Transplant Institute, Rotterdam, The Netherlands

   Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center, Rotterdam, The Netherlands

5. Ron H. N. van Schaik

   Erasmus MC

   Affiliation as printed

   Clinical Chemistry Erasmus University Medical Center Rotterdam The Netherlands

   Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands

6. Marc A G J ten Dam

   Canisius-Wilhelmina Ziekenhuis

   Affiliation as printed

   Department of Internal Medicine Canisius Wilhelmina Hospital Nijmegen The Netherlands

   Department of Internal Medicine, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands

7. Marije C. Baas

   Radboud University Nijmegen · Radboud University Medical Center

   Affiliation as printed

   Department of Nephrology Radboud University Medical Center Nijmegen The Netherlands

   Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands

8. Luuk B. Hilbrands

   Radboud University Nijmegen · Radboud University Medical Center

   Affiliation as printed

   Department of Nephrology Radboud University Medical Center Nijmegen The Netherlands

   Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands

9. Teun van Gelder Aachen Department of Clinical Pharmacy and Toxicology Leiden University Medical Center Leiden The Netherlands Department of Clinical Pharmacy and Toxicology

   Leiden University Medical Center · Erasmus MC · Erasmus University Rotterdam

   Affiliation as printed

   Department of Clinical Pharmacy and Toxicology Leiden University Medical Center Leiden The Netherlands

   Internal Medicine Division of Nephrology and Transplantation Erasmus University Medical Center Rotterdam The Netherlands

   Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands

   Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center, Rotterdam, The Netherlands