In cases of ulcerative colitis where inflammation is limited to the rectum or distal colon, suppositories or enemas with 5-ASA, SASP, and steroids are used as topical preparations in addition to oral 5-ASA and SASP preparations . In particular, foam formulations of steroids have been widely used and have become an effective treatment for local ulcerative colitis . However, there are some cases in which these treatments fail to induce a response. Currently, the next-stage treatments include the systemic application of steroids, azathioprine, and biological agents, which are associated with many complications [14–16]. Systemic treatment of ulcerative colitis, which is localized to proctitis or distal colitis, could be an excessive measure. Therefore, in this study, we focused on tacrolimus as a new topical formulation. Some reports showed that tacrolimus, as a topical preparation, has therapeutic effects in the treatment of localized ulcerative colitis [17–19]. However, transrectal drug administration could lead to absorption through the mucous membrane. In a previous report, many cases with elevated blood levels of tacrolimus were registered, and the value of local therapy has not been strictly examined. In another study, tacrolimus was orally or transanally administered to normal volunteers, and the blood concentration was measured. In this study, the duration and amount of the maximum blood tacrolimus concentration were lower in cases with transanal administration than in those cases with oral administration; however, a certain amount of tacrolimus was absorbed into the bloodstream in both cases. Thus, transanal administration of tacrolimus could lead to clinically relevant systemic exposure . Furthermore, absorption efficiency is considered to be higher in patients with ulcerative colitis who have erosions or ulcers in the rectum. As such, blood level monitoring is required for a rigorous evaluation of the safety and efficacy of the transanal administration of tacrolimus as local therapy. Therefore, in this study, we measured the blood concentration of tacrolimus 2 weeks after the start of the administration of the tacrolimus suppositories and every 4 weeks thereafter and verified the effect of the drug by closely monitoring the blood concentration. The therapeutic effect in this study was seen as a significant improvement in the pMayo score between baseline and 2 or 4 weeks after the initiation of therapy, indicating the usefulness of tacrolimus suppositories. The therapeutic effect was seen in 12 out of 16 cases, where the blood concentration of tacrolimus did not exceed the detectable limit of 2.0 ng/ml. On the other hand, even when the blood concentration of tacrolimus is below the detectable limit, a small amount of tacrolimus could be absorbed, and such a low dose could produce therapeutic benefits in ulcerative colitis. Although an accurate evaluation of this was difficult to achieve in this study, we showed that, even when there is no improvement in symptoms, inflammation is reduced on the anus side of the rectum, and the range of topical drug delivery could be reached (Fig. 2). This observation highlights the value of tacrolimus suppositories as a topical formulation.
Regarding the optimal dose of tacrolimus, 9 out of 16 cases showed an improvement with 0.5 g of tacrolimus, which was the minimum dose used in this study. As none of these cases exceeded the measurable serum level of tacrolimus, we recommend treatment at this dose. Symptom improvement was seen in 3 out of the 6 cases when the tacrolimus suppository was increased to 1 g or more. However, in one of these cases, the blood concentration was higher than the lower limit of measurement, and the administration of tacrolimus was discontinued. In 3 other cases, no effect was seen even when the dose was increased to 1 g or more. Transanal tacrolimus doses of 1 g or more could also be considered for the treatment of ulcerative colitis after evaluating the risks and benefits. However, no adverse events were observed in any cases during the study period, including cases with elevated blood tacrolimus concentrations. We believe that adverse events were prevented because appropriate measures such as discontinuation and dose reduction were judiciously implemented. Additionally, in one case, the administration of tacrolimus was continued up to 96 weeks but no exacerbation of adverse events was observed, further demonstrating the safety of transanal tacrolimus administration with appropriate blood concentration monitoring. Furthermore, regarding the position of tacrolimus suppositories as a topical preparation, a single comparative study of transanal tacrolimus and steroids reported that tacrolimus suppository formulations were comparable to transanal steroids therapy . In this study, topical preparations were not used in 7 patients at the start of the study, and 6 out of 7 patients showed improvement with tacrolimus suppository administration. Of the five cases that switched from topical mesalazine preparations, 4 cases showed improvement with tacrolimus suppository administration. In contrast, of the 4 cases that switched from topical steroid preparations, 2 cases showed improvements with tacrolimus suppository administration. Although the number of cases was small and could not be considered statistically relevant, tacrolimus was highly effective in cases where topical drugs were not used or switched from the mesalazine suppository, while its therapeutic effect was limited in cases where steroids were previously used. This observation is consistent with those reported in previous studies. Steroid suppositories were effective in some cases where tacrolimus suppositories were ineffective. The effect of tacrolimus suppositories was superior and similar to that of mesalazine topical preparation and steroids suppository, respectively. Further studies are required to validate this observation.