Tacrolimus exposure early after lung transplantation and exploratory associations with acute cellular rejection.

Abstract

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)Lh-1, and the median C0 12.7 (9.9-16.6)μgL-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)Lh-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.