Effect of Mild Diarrhea on Tacrolimus Exposure

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Introduction: Diarrhea is a frequent adverse event in patients treated with the combination of tacrolimus and mycophenolate mofetil (MMF) and can have an important impact on the pharmacokinetics of tacrolimus. In case of severe diarrhea, the exposure to tacrolimus (area under the curve, AUC) can be increased several fold and is reflected in a substantial increase in trough levels. Mild diarrhea (2-3 stools per day) is more common and not always reported to the treating physician. It is unknown whether ongoing mild diarrhea may result in unnoticed chronic tacrolimus overexposure leading to irreversible nephrotoxicity. Therefore the aim was to assess the degree of tacrolimus over-exposure in renal transplant patients with mild diarrhea while on treatment with tacrolimus and MMF. Methods: 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. To measure the 12 hours AUC, intensive pharmacokinetic sampling for tacrolimus was performed at two occasions in each subject. Tacrolimus levels were assessed by a validated dried blood spot method for sampling and measurement. Pharmacokinetic parameters were assessed with noncompartmental methods. Participants completed two questionnaires on gastro-intestinal discomfort, the GIQLI and GSRS. Results: The mean daily dose of tacrolimus was 6 mg (SD 3.3) in the group with mild diarrhea and 7.1 mg (3.6) in the controls, with no significant difference in trough levels (9.6 μg/L (95% CI 8.6-10.9) versus 8.3 μg/L (6.9-9.9)). The dose-adjusted 12 hour exposure to tacrolimus was 70.4 μg.h/L.mg (52.7-93.9) in the patients with mild diarrhea and 55.0 μg.h/L.mg (41.6-72.7) in the controls (NS). The scores on items related to diarrhea of the GSRS and GIQLI were respectively 4.3(2.0) and 7.3 (2.8) in patients with diarrhea and 2.3 (0.5) and 9.8 (1.4) for the controls (P< 0.01 and P< 0.05, as expected). Moreover, there was no significant correlation between the scores on diarrhea related items of the GSRS and GIQLI on the one hand and the dose-adjusted AUC of tacrolimus on the other hand. The intra-individual variability in tacrolimus exposures was limited and not affected by the presence of mild diarrhea. Conclusion: We found no evidence for the presence of unnoticed tacrolimus overexposure in patients with mild diarrhea while on treatment with tacrolimus and MMF. Measuring tacrolimus trough level seems to suffice for the prevention of substantial overexposure in these patients.

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