Effect of Mild Diarrhea on Tacrolimus Exposure

Diarrhea is a frequent adverse event in patients treated with the combination of tacrolimus and mycophenolate mofetil (MMF). In case of severe diarrhea, the total exposure to tacrolimus can substantially increase, which is reflected in a rise of the predose trough level (C0). In mild diarrhea (two to three stools per day), an increased exposure might occur without trough levels exceeding the target range, resulting in "silent" chronic tacrolimus overexposure. The aim was to assess the degree of unnoticed tacrolimus overexposure in renal transplant patients with mild diarrhea while on treatment with tacrolimus and MMF. A prospective pharmacokinetic study was performed in 12 recipients of a renal allograft using a combination of tacrolimus and MMF with mild diarrhea and in 12 controls. Tacrolimus levels were assessed by a validated dried blood spot method for sampling and measurement. The C0 did not differ between patients with mild diarrhea and controls (mean [95% confidence interval], 9.6 µg/L [8.6-10.9 µg/L] and 8.3 µg/L [6.9-9.9 µg/L]). In addition, there was no significant difference in the 12-hr area under the curve between patients with mild diarrhea and controls (185.6 µg· h/L [153.6-224.2 µg·h/L] vs. 170.5 µg·h/L [137.2-221.8 µg·h/L]). As a result, the ratio between the 12-hr area under the curve and C0 was similar in both groups (19.2 [17.5-21.1] vs. 20.6 [19.0-22.4]). The intraindividual variability in tacrolimus exposure was limited and not affected by the presence of mild diarrhea. We found no evidence for the presence of hidden tacrolimus overexposure in patients with mild diarrhea while on treatment with tacrolimus and MMF.