Tacrolimus exposure early after lung transplantation and exploratory associations with acute cellular rejection
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To (i) describe tacrolimus (TAC) pre-dose concentrations (C0), (ii) calculate apparent oral TAC clearance (CL/FHCT) adjusted for measured haematocrit (HCTi) and standardised to a HCT of 45%, across three observation time points and (iii) explore if low TAC C0 or high mean CL/FHCT are associated with an increased risk of rejection episodes early after lung transplantation.
TAC whole blood concentration-time profiles and transbronchial biopsies were performed prospectively at weeks 3, 6 and 12 after lung transplantation. The TAC pre-dose concentration (C0) was measured, and CL/FHCT was determined using non-compartmental analysis. The associations between TAC C0 and CL/FHCT and rejection status were explored using repeated measures logistic regression.
Eighteen patients provided 377 TAC whole blood concentrations. Considerable variability around the median (IQR) CL/FHCT 6.8 (4.2–15.9) L h−1, and the median C0 12.7 (9.9–16.6) μg L−1 was noted. Despite adjustment for haematocrit, a significant decrease was observed in CL/FHCT in all patients over time: CL/FHCT 14 (5.4–23) at week 3, CL/FHCT 7.7 (4.5–12) at week 6 and CL/FHCT 3.9 (2.4–11) L h−1 at week 12 (p < 0.01). Seven (38.9%) patients experienced a single grade 2 rejection, whilst 11 (61.1%) patients experienced no rejection. Higher TAC C0 were associated with a reduced risk of rejection OR 0.68 (95% CI 0.51–0.91, p = 0.02), and greater mean CL/FHCT was associated with an increased risk of rejection OR 1.34 (95% CI 1.01–1.81 p = 0.04).
Monitoring TAC C0, HCT and CL/FHCT in patients after lung transplantation may assist clinicians in detecting patients at risk of acute rejection and may guide future research into TAC and HCT monitoring after lung transplantation.
KeywordsTacrolimus Lung transplantation Exposure Clearance Rejection
Chronic lung allograft dysfunction
Therapeutic drug monitoring
The authors thank Dr. Ross Norris from St Vincent’s Pathology for performing the tacrolimus assays.
Dr. David Darley was the primary investigator and first author of the article. Lilibeth Carlos assisted with patient consent, data collection and analysis. Dr. Stefanie Hennig and Zhixin Liu assisted with data analysis. Prof Ric Day assisted with study design. All authors contributed to manuscript review. Prof Allan Glanville provided supervision and funding for the study.
Funding for the TAC assays was provided by the Department of Thoracic Medicine, St Vincent’s Hospital, Darlinghurst.
Compliance with ethical standards
This material has not been published previously (except for interim results in abstract form), is not under consideration and has not been accepted for publication elsewhere. All authors listed on the manuscript have seen and approved the submission of this version of the manuscript. I believe the submission complies with the manuscript checklist. I will be serving as the principal author for correspondence purposes.
Conflict of interest
The authors declare that they have no conflict of interest.
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