Introduction: Acute cellular rejection (ACR) in small bowel transplant recipients is expected to increase intestinal permeability and to reduce intestinal CYP3A/p-glycoprotein activity. These changes may increase blood concentrations of tacrolimus and result in acute toxicity. We evaluated the impact of ACR episodes on dose-normalized tacrolimus blood concentrations in intestinal transplant recipients.

Methods: Adult intestinal transplant recipients who had ACR from 02/1998 to 07/2013 at a single center were reviewed. Patient history, ACR information, laboratory values, and drug dosing were collected. Changes in dose-normalized tacrolimus levels were assessed starting 30 days before, during, and up to 30 days after documented ACR resolution. Secondary outcomes included evaluating impact of ACR grade, ACR treatment, time post-transplantation, and initial or recurrent episode.

Results: 285 ACR episodes in 113 intestinal transplant recipients were included in the analysis. Median dose-normalized concentrations were different before, during, and after ACR (1.7ng/mL/mg vs. 4.0ng/mL/mg vs. 2.2ng/mL/mg, p=0.014). Median percent change in dose-normalized tacrolimus was significantly different across ACR severity (p=0.014), time post-transplant (p=0.007), and initial versus recurrent ACR (p=0.013). SCr was significantly higher during ACR (1.3mg/dL vs. 1.5mg/dL vs. 1.2mg/dL, p=0.001). Dose-normalized tacrolimus concentrations were elevated during ACR and this was associated with the increase in SCr.

Conclusion: There is potential for increased systemic exposure and toxicity of tacrolimus and other orally administered drugs in small bowel transplant patients during ACR. Further pharmacokinetic investigation is warranted.

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