Variability in whole blood tacrolimus concentrations after oral and continuous intravenous administration in the early post-lung transplantation period: a retrospective multicenter cohort study

Abstract

BACKGROUND: A relationship between high tacrolimus variability after lung transplantation (LTx) and an increased risk for rejection of the allograft or nephrotoxicity is increasingly suggested in literature. The highly variable bioavailability of tacrolimus after oral administration is thought to play a predominant role. In the clinical practice,there is no consensus on the optimal administration route, early after LTx,to obtain a reduced variability. OBJECTIVE: The purpose is to investigate the effect of continuous intravenous and oral administration on tacrolimus variability early after lung transplantation. METHODS: In this retrospective study, 224 patients received intermittent oral administration of tacrolimus and 298 received continuous intravenous administration. Intra-patient variability (IPV) and the time within the therapeutic range (TTR) were calculated using daily tacrolimus whole blood concentrations from the first 14 days after LTx. Linear regression was used to investigate the effect of the administration route on variability. RESULTS: The mean IPV in the intravenous group, weighted for the number of samples available per patient, was 29.2% ± 10.9 compared to 31.7% ± 10.5 in the oral group, with a difference of 2.5% [95% Confidence Interval (CI) 2.0-3.1]. After adjusting for effect modifiers, the mean IPV in the intravenous group was 20.2% and 28% in the oral group, indicating a 7.8% difference [95% CI 5.3-10.4]. The unadjusted median TTR in the intravenous group was 30.7% (18.7-41.1) and in the oral group 23.6% (13.0-30.8). Univariate analysis showed a mean TTR in the intravenous group of 30.7% and of 23.6% in the oral group, showing a difference of -7.1% [95% CI -7.9 - -6.2]. After adjustment, TTR was 13.3% in the oral group and 27.7% in the intravenous group. Thus, the oral TTR was 14.4% lower than the intravenous TTR [95% CI -22.1 - -6.8]. CONCLUSION: The variability in tacrolimus concentrations, measured as IPV and TTR, is higher when tacrolimus is administered orally in the first 14 days after LTx in comparison to continuous intravenous infusion, with a switch to oral administration once the patient is more stable.