NIV Congres

Background Tacrolimus has a narrow therapeutic window and therefore requires therapeutic drug monitoring (TDM), which is usually performed by measuring trough levels before ingestion of the morning dose. In daily clinical practice, it is logistically difficult to measure trough levels in patients who use tacrolimus twice daily and visit the outpatient clinic in the afternoon. The slow-release formulation of tacrolimus (QD) is taken once daily in the morning and has a terminal elimination half-life time of 37.8 h. Therefore, trough levels measured in the afternoon may be close enough to morning trough levels, which would be convenient for patients visiting the outpatient clinic in the afternoon. Alternatively, the target range for trough levels measured in the afternoon should be adjusted.

Aim To assess whether measurement of the trough level can be delayed from the morning to the afternoon in renal transplant patients with tacrolimus QD taken in the morning.

Methods and patients We measured tacrolimus pharmacokinetics in 13 patients using tacrolimus QD (ADVAGRAF^®). The target range of the trough level was between 5 and 10 ug/L. In each patient, eleven blood samples were drawn during a period of 32 hours after the intake of tacrolimus QD by use of the validated dried blood spot method. Tacrolimus levels were measured with HPLC-tandem mass spectrometry.

Results The mean interval after transplantation was 74 months (range 25-178). The mean daily dose of tacrolimus QD was 5 mg (1.5-9). The 24-hour exposure (area under the curve) to tacrolimus was 308.5 ug.h/L (standard deviation 72.0). The trough levels at 24, 26, 28, 30 and 32 hours after ingestion were 9.1 ug/L (2.1), 8.2 ug/L (1.9), 8.1 ug/L (1.8), 7.7 ug/L (1.9), and 7.1 ug/L (1.6), respectively. Trough levels at 24 hours and at 32 hours differed significantly (p<0.001). The Pearson correlation coefficient between trough levels and area under the curve was 0.91, 0.90, 0.89, 0.92 and 0.89 for trough levels taken at 24, 26, 28, 30 and 32 hours, respectively (p<0.001 at each timepoint).

Conclusion Delayed trough level measurement provides significantly lower values and therefore requires adjustment of the target range. However, the persisting strong correlation between trough levels taken until 32 hours after ingestion and 24-hour exposure warrants the use of delayed trough level measurement to improve patient convenience.