Systemic Tacrolimus Research Articles

Effect of inhaled tacrolimus on ischemia reperfusion injury in rat lung transplant model

Systemic tacrolimus therapy has been shown to protect against lung ischemia-reperfusion injury in animal models. We sought to investigate on a functional and cellular level if inhaled nanoparticle tacrolimus administered to the donor lung before procurement could similarly attenuate ischemia-reperfusion injury after lung transplant. An isogenic orthotopic rat model of single left lung transplant was used. Donor animals were pretreated with inhaled tacrolimus (treatment group) or inhaled lactose (controls) before lung procurement. Lung grafts were subjected to 3 hours of cold ischemia followed by 4 hours of reperfusion after graft implantation. Recipient animal arterial blood gas measurement and isograft wet to dry weight ratios were obtained. Macrophage, neutrophil, and T-cell accumulation and activation in lung isografts, including γδ T-cell, T-helper, and cytotoxic T-cell subtypes were analyzed by flow cytometry. Tacrolimus levels were measured in the lung isograft using liquid chromatography/mass spectrometry. Isograft cytokine levels were measured with commercial enzyme-linked immunosorbent assay and microbead array kits. Oxygenation in treatment group animals was significantly higher than in controls. The presence of macrophages, neutrophils, and all T-cell subtypes in the isografts as well as isograft levels of inflammatory cytokines were all less in the treatment group versus controls, although no single variable achieved statistical significance. Inhaled nanoparticle tacrolimus treatment of lung donors is associated with an attenuation of ischemia-reperfusion injury on a functional and cellular level in lung transplant.

Impact of CYP3A5 Genotype on Tacrolimus Versus Midazolam Clearance in Renal Transplant Recipients: New Insights in CYP3A5-Mediated Drug Metabolism

In vitro studies have identified both midazolam and tacrolimus as dual CYP3A4 and CYP3A5 substrates. In vivo; however, the CYP3A5 genotype has a marked impact on tacrolimus pharmacokinetics, whereas it seems not to affect midazolam pharmacokinetics. The aim of the current study was to explore this paradigm in a relevant clinical setting. A case-control study in 80 tacrolimus-treated renal transplant recipients comparing systemic and apparent oral midazolam clearance and tacrolimus pharmacokinetics in CYP3A5 expressers (CYP3A5*1 allele carriers) and CYP3A5 nonexpressers (CYP3A5*3/*3) was performed. CYP3A5 expressers display an approximately 2.4-fold higher tacrolimus clearance as compared with CYP3A5 nonexpressers, whereas there are no differences in systemic and apparent oral midazolam clearance. These data confirm that in vivo CYP3A5 plays an important role in tacrolimus metabolism, while its contribution to midazolam metabolism in a relevant study population is limited. Furthermore, these data suggest that midazolam is to be considered as a phenotypic probe for in vivo CYP3A4 activity rather than combined CYP3A4 and CYP3A5 activity.

Targeting the Kv1.3 potassium channel for immunosuppression in vascularized composite allotransplantation - a pilot study

Kv1.3-channels are critically involved in activation and function of effector memory T cells. Blocking Kv1.3-channels was investigated for its effect on skin rejection in a rat limb-transplantation-model. Animals received the Kv1.3-blocker correolide C systemically or locally as intra-graft-treatment in combination with tacrolimus. Systemic (intraperitoneal) administration of correolide C resulted in slight, but significant prolongation of allograft survival compared with untreated and placebo treated controls. In 4/6 correolide C treated animals, histology showed an intact epidermis and a mild infiltrate by day 10. High correolide C plasma trough levels correlated with prolonged allograft survival. A decrease in CD4+ and CD8+ effector memory T cells was observed in allograft skin, peripheral blood and the spleen on day 5. When applied subcutaneously in combination with systemic tacrolimus (30days+/-anti-lymphocyte serum) detectable, but insignificant prolongation of graft survival was achieved. 2/5 animals showed an intact epidermis and a mild infiltrate until day 45. Tapering systemic tacrolimus and weaning on day 50 resulted in rejection by day 55, regardless of local correolide C treatment. Subcutaneous injection did not lead to systemic plasma levels. The Kv1.3-channel is a potential drug target worth exploring in more detail for immunosuppression in vascularized composite allotransplantation.

Development of Potential Orphan Drug Therapy of Intravesical Liposomal Tacrolimus for Hemorrhagic Cystitis Due to Increased Local Drug Exposure

The potent immunosuppressive effect of systemic tacrolimus is limited by the high incidence of severe adverse effects, including nephrotoxicity and hypertension. Intravesical application of tacrolimus is hindered by its poor aqueous solubility, justifying the search for novel delivery platforms such as liposomes. We evaluated the pharmacokinetics of tacrolimus encapsulated in liposomes (lipo-tacrolimus), which is being developed as a potential orphan drug indication for hemorrhagic cystitis. A single dose of lipo-tacrolimus was instilled in the bladder with the rat under anesthesia. Also, tacrolimus was instilled intravesically or injected intraperitoneally in other rat groups. The tacrolimus dose was constant in all formulations at 200 μg/ml. At different times blood, urine and bladder samples were collected and stored at -80C until analysis. Tacrolimus levels in samples were analyzed using microparticle enzyme immunoassay II. The AUC of lipo-tacrolimus in serum at 0 to 24 hours was significantly lower than that of tacrolimus instillation or injection. Noncompartmental pharmacokinetic data analysis revealed maximum concentration of lipo-tacrolimus and tacrolimus in serum and urine at 1 and at 2 hours, respectively. Urine AUC(0-24) after intravesical administration was significantly higher than in the intraperitoneal group (p <0.05). Bladder tacrolimus AUC(0-24) did not differ significantly between the groups. Single dose pharmacokinetics revealed that bladder instillation of liposome encapsulated tacrolimus significantly decreased systemic exposure to instilled tacrolimus as well as vehicle related toxicity. Intravesical liposomal tacrolimus may be a promising approach as an orphan drug indication for hemorrhagic cystitis.

Measurement and Compartmental Modeling of the Effect of CYP3A5 Gene Variation on Systemic and Intrarenal Tacrolimus Disposition

We evaluated the hypothesis that cytochrome P450 3A5 (CYP3A5) expression can affect intrarenal tacrolimus accumulation. Tacrolimus was administered orally to 24 healthy volunteers who were selected on the basis of their CYP3A5 genotype. As compared with CYP3A5 nonexpressors, expressors had a 1.6-fold higher oral tacrolimus clearance and 2.0- to 2.7-fold higher metabolite/parent area under the curve (AUC) ratios for 31-desmethyl tacrolimus (31-DMT), 12-hydroxy tacrolimus, and 13-desmethyl tacrolimus (13-DMT). In addition, the apparent urinary tacrolimus clearance was 36% lower in CYP3A5 expressors as compared with nonexpressors. To explore the mechanism behind this observation, we developed a semiphysiological model of renal tacrolimus disposition and predicted that tacrolimus exposure in the renal epithelium of CYP3A5 expressors is 53% of that for CYP3A5 nonexpressors, when normalized to blood AUC. These data suggest that, at steady state, intrarenal accumulation of tacrolimus and its primary metabolites will depend on the CYP3A5 genotype of the liver and kidneys. This may contribute to interpatient differences in the risk of tacrolimus-induced nephrotoxicity.

Conjunctival Squamous Cell Carcinoma following Psoriasis Treatment

Psoriasis is a relatively common inflammatory disease of the skin and joints. Moderate to severe psoriasis often necessitates lifelong alternating systemic therapies, many of which may increase the risk of nonmelanoma skin cancers and lymphoproliferative disorders. A 34-year-old male was diagnosed with squamous cell carcinoma (SCC) involving the right lower bulbar and palpebral conjunctiva with extension to the proximal lacrimal drainage system. The patient had suffered from severe psoriasis since childhood, for which he was on long-standing systemic cyclosporine, topical tacrolimus, and previous phototherapy. Margin-controlled excision of the lower half of the bulbar conjunctiva and lower eyelid with subsequent reconstruction was performed, followed by adjunctive topical mitomycin C 0.04% drops and local interferon injections. Cyclosporine was replaced with oral prednisolone. The patient was free of recurrence of SCC at 18 months. Although conjunctival SCC has been described following cyclosporine treatment for organ transplantation, this report describes a case of conjunctival SCC following lower-dose cyclosporine treatment for psoriasis in a patient who had previous psoralen plus ultraviolet A (PUVA) treatment. The conjunctival SCC should be considered in the differential diagnosis of new conjunctival lesions in such patients.

Systematic review: the role of tacrolimus in the management of Crohn’s disease

BACKGROUND Several published studies have evaluated the efficacy of tacrolimus in the management of Crohn's disease with variable conclusions. AIM To review systematically the evidence examining the efficacy and safety of tacrolimus in treating Crohn's disease. METHODS The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (PUBMED) and EMBASE (1984 to January 2011) were searched. Also, references from selected articles were examined. Case series (five or more patients), cohort and randomised controlled trials were eligible for inclusion, incorporating oral, intravenous or topical tacrolimus therapy. The primary outcome was induction of remission of active Crohn's disease. RESULTS Eleven studies met the inclusion criteria which included 163 patients, of which 127 received tacrolimus therapy. In patients with luminal Crohn's disease, the crude pooled remission rate for tacrolimus was 44.3% (range, 7-69%) and the crude pooled response rate was 37.1% (range, 14-57%). For patients with perianal disease using systemic tacrolimus, crude pooled remission rate was 28.6% (range, 0-64%) and crude pooled response rate was 38.8% (range, 0-57%). Combining data from two studies using topical tacrolimus, 35.7% of patients achieved remission and 28.6% partial response. Nonserious adverse effects are common, particularly tremor, paraesthesia and headache. Reversible nephrotoxity occurred in 16% of patients. CONCLUSIONS The current evidence; although of a poor quality, appears to support the use of tacrolimus in Crohn's disease. High quality randomised controlled trials are needed.

Poor efficacy of oral tacrolimus in the treatment of severe generalized atopic eczema in adults: A small retrospective case series

We report a small, but novel case series of four adults with severe generalized atopic eczema (AE) not responsive to several other immunomodulatory therapies, who were treated with oral tacrolimus (5 mg twice-daily). Three of the four patients failed therapy with systemic tacrolimus, despite two of these showing an initial clinical response; the fourth patient remains on tacrolimus monotherapy with good control of skin disease. Although oral tacrolimus was well-tolerated in this small group of adults, the clinical efficacy in this series for severe AE was poor. Tacrolimus may yet have a role in less severe disease, but larger prospective studies are required to qualify its place as a treatment option in AE.

Tacrolimus in the Treatment of Ocular Diseases

Tacrolimus (FK506) has been used successfully as a systemic immunomodulator for more than 2 decades, and numerous studies have investigated its mechanisms of action. Systemic and topical tacrolimus have been investigated as treatments for ocular surface disorders that may have an immune-based inflammatory component. In these studies, tacrolimus has shown efficacy in corneal graft rejection, inflammatory conjunctival and corneal diseases, uveitis, and graft-versus-host disease. As these disorders are often refractory to other available treatments, ophthalmic or systemic tacrolimus is a welcome nontoxic adjunct or replacement to potentially toxic topical or systemic immunosuppressive therapies.

Local Immune Regulation of Mucosal Inflammation by Tacrolimus

PurposeTacrolimus is a potent immunomodulator that is effective in the treatment of inflammatory bowel disease (IBD). However, potential toxicity and systemic effects with oral intake limit its use. Local tacrolimus treatment is effective in a subgroup of proctitis patients. This study aimed to evaluate whether colonic mucosal immune cells are susceptible to locally applied tacrolimus in vitro. Our in vivo studies aimed at evaluating whether local tacrolimus treatment in mice would bring about local immune suppression and to compare colonic and systemic tacrolimus levels after locally and systemically applied tacrolimus.ResultsIn vitro tacrolimus inhibited the activation of multiple cell types present in colonic tissue; lamina propria T cells, NKT cells, and both classical- and non- classical antigen presenting cells. However, the cytokine production of epithelial cells was not inhibited by tacrolimus at these concentrations. After rectal administration in mice, tacrolimus blood levels were comparable to those obtained by oral intake. However, rectally treated mice exhibited a 14-fold higher concentration of tacrolimus within their colonic tissue than orally treated mice. Moreover, rectally applied tacrolimus resulted in a local but not a systemic immune suppression in mice.ConclusionsTacrolimus inhibits activation of several pivotal immune cells of the intestinal mucosa. Murine studies indicate that colonic application of tacrolimus induces local rather than systemic immune suppression.

Long-term safety of tacrolimus ointment in atopic dermatitis

Background: Tacrolimus ointment has shown efficacy as monotherapy in both short- and long-term studies in atopic dermatitis. Absorption of tacrolimus after topical application is dependent on the barrier function of the skin. Absorption through the intact epidermis is very low and eczematic skin a little higher. In comparison to systemic tacrolimus used for prevention and treatment of rejection after organ transplantation, the bioavailability of topical tacrolimus in patients with atopic dermatitis is between 3 and 4%. Long-term safety studies of up to 4 years have not shown adverse events associated with systemic use of immunosuppressive agents, that is, increased risk of infections, lymphomas or skin cancers. Despite these findings, many physicians remain concerned about possible long-term malignancies associated with long-term treatment with a topical calcineurin inhibitor. Objective: To identify in the published literature possible long-term safety issues associated with topical tacrolimus treatment. Methods: PubMed was used to identify studies of atopic dermatitis therapy in which tacrolimus ointment was used for at least 6 months. We evaluated the safety data available from these studies. In addition, some safety data were evaluated from clinical follow-up of our own patients who have used tacrolimus ointment intermittently for up to 14 years. Conclusions: During a follow-up period of 4 years in clinical studies, no increased risk of infections or cancer was associated with long-term use of tacrolimus ointment. Only short-term adverse events were detected. They included increased burning and stinging of the skin, and a temporary increase in skin infections. No signs of immunosuppression were observed after 1 – 4 years of intermittent treatment with tacrolimus ointment.

The pharmacokinetics of tacrolimus after first and repeated dosing with 0.03% ointment in infants with atopic dermatitis*

In adults and children aged > 2 years, systemic absorption of tacrolimus from tacrolimus ointment is very low. In this study, the pharmacokinetics of tacrolimus 0.03% ointment were investigated in infants aged 3-24 months. The pharmacokinetics of tacrolimus after first and repeated topical application of tacrolimus 0.03% ointment were evaluated in 53 infants (age, 3-24 month) with atopic dermatitis requiring treatment with mid-potency topical corticosteroids. Patients were grouped according to percentage of body surface area affected (Group 1: 5-20%; Group 2: > 20-40%; Group 3: > 40%). After stratification, patients were randomized (double-blind) to receive once-daily or twice-daily tacrolimus 0.03% ointment. Blood samples taken on days 1 and 14 (first and last application) showed minimal systemic tacrolimus exposure. Overall, 97% of blood samples assayed contained tacrolimus concentrations < 1 ng/ml, and 20% were below the lower limit of quantification (0.025 ng/ml). Systemic tacrolimus exposure was variable, but tended to increase as the treated body surface area increased. Mean apparent half-life of tacrolimus was 80 +/- 35 h (range: 25-175 h). Most patients experienced substantial clinical improvement in their atopic dermatitis. There were no clinically significant changes in laboratory values, and the most frequently reported adverse events were minor infections and local skin irritations. Tacrolimus 0.03% ointment in infants is associated with very low systemic exposure to tacrolimus. Treatment was well tolerated and led to considerable clinical improvement.

Skin and systemic pharmacokinetics of tacrolimus following topical application of tacrolimus ointment in adults with moderate to severe atopic dermatitis

Systemic exposure to tacrolimus following topical application of tacrolimus ointment is minimal. There are, however, no data on the distribution of tacrolimus in the skin. To assess the distribution of tacrolimus in the skin and the systemic pharmacokinetics of tacrolimus in adults with moderate to severe atopic dermatitis after first and repeated application of tacrolimus ointment. We investigated skin distribution of topically applied tacrolimus and systemic pharmacokinetics of percutaneously absorbed tacrolimus in adults with atopic dermatitis after topical application of tacrolimus 0.1% ointment twice daily for 2 weeks. Tacrolimus concentrations were assessed in full-thickness skin biopsies and blood samples. Of 14 patients, 11 completed treatment and were analysed. Mean +/- SD tacrolimus concentrations in the skin at 24 h after first and last ointment applications were 94 +/- 20 and 595 +/- 98 ng cm(-3), respectively. At 168 h after stopping treatment, values were 97% lower than at 24 h after last application. Tacrolimus concentration decreased with increasing skin depth. Systemic tacrolimus exposure after ointment application was low and highly variable, with 31% of samples below the limit of quantification (0.025 ng mL(-1)) and 94% below 1 ng mL(-1). Blood concentrations at 24 h after the first and last ointment applications were 750 and 1800 times lower, respectively, than those in skin. Physicians' assessments showed that tacrolimus ointment was effective and well tolerated. Tacrolimus was primarily partitioned in the skin, with minimal systemic absorption after topical application, in patients with atopic dermatitis.

Use of Systemic T-lymphocyte Signal Transduction Inhibitors in the Treatment of Atopic Keratoconjunctivitis

Topical immunomodulators such as tacrolimus have revolutionized the treatment of atopic dermatitis. Because T lymphocytes are integral to the pathogenesis of atopic dermatitis, systemic treatment with T-lymphocyte signal transduction inhibitors should ameliorate both the dermatologic and ocular manifestations. We describe the successful treatment of 6 patients with severe atopic keratoconjunctivitis (AKC) resistant to conventional therapies. Retrospective observational case series. The charts of patients with AKC assessed by 1 of the authors were reviewed to identify those treated with systemic T-cell signal transduction inhibitors. Visual acuities, previous treatments, and the response to systemic signal transduction inhibitors were observed and reported in 6 patients. The patients had a mean duration of AKC of 21 years. Topical corticosteroids and antihistamines had failed to control signs and symptoms of the disease in all patients, and in some patients, systemic corticosteroids and topical cyclosporine were ineffective. Three patients were treated with systemic cyclosporine, and 3 were treated with systemic tacrolimus. One patient was subsequently treated with daclizumab in addition to tacrolimus. All 6 patients experienced complete remission of their AKC and an increase in visual acuity. Selective systemic immunosuppression of T lymphocytes with cyclosporine or tacrolimus has proved effective in the treatment of both atopic dermatitis and atopic keratoconjunctivitis. We advocate the consideration of systemic therapy in cases that are resistant to conventional treatment to resolve inflammation and preserve vision. Further studies in this area are advocated.

Metastatic Crohn's disease: a review

Metastatic Crohn's disease (MCD) indicates the presence of non-caseating granuloma of the skin at sites separated from the gastrointestinal tract by normal tissue and is the least common dermatologic manifestation of CD. In adults, MCD usually appears after the initial diagnosis of CD in 70% of cases, whereas in children, it appears at the same time as CD in almost half of the cases. The most frequent skin lesions in adults are nodules, plaques with or without ulceration on the extremities and ulcers on the genitals. In children, genital swelling with or without erythema is the most frequent presentation of MCD. Simultaneous presence of perianal CD affects more females (60%) and particularly children. Associated gastrointestinal symptoms are present in one third of the cases in adults and in half of the cases in children. Treatment is often unsatisfactory. Randomised controlled trials are lacking. Various chemotherapeutic agents have been used such as oral metronidazole, topical and/or oral steroids, azathioprine, cyclosporine, sulfasalazine, tetracyclines, topical or systemic tacrolimus, infliximab alone or with methotrexate, and surgical treatment with oral zinc sulphate. MCD represents another 'great imitator'. This reviews the most relevant characteristics of this disease, in order to increase awareness and to avoid delay in diagnosis and improve management of the whole CD complex.

Conjunctival Intraepithelial Neoplasia in a Patient Treated with Tacrolimus After Liver Transplantation

To report a case of conjunctival intraepithelial neoplasia in a patient treated with tacrolimus after liver transplantation for hepatic carcinoma. Description of the initial clinical presentation of a patient, tumor management, and 15-month follow-up. A 70-year-old man presented with a conjunctival intraepithelial neoplasia that developed on the site of a preexisting pterygium. After total surgical removal and additional application of mitomycin, local tumor control was achieved. We describe a case of intraepithelial conjunctival neoplasia in a patient treated with systemic tacrolimus. Local tumor control was achieved at 15 months after appropriate surgical management.

The safety of tacrolimus ointment for the treatment of atopic dermatitis: a review

Tacrolimus ointment is a topical calcineurin inhibitor (TCI) that was developed specifically for the treatment of atopic dermatitis (AD). It is one of the most extensively tested dermatological products, with more than 19 000 patients (including approximately 7600 children) having participated in the tacrolimus ointment clinical development programme. Recent regulatory reviews have focused on the potential risk of malignancy with TCIs, based on their mode of action and the effects of systemic tacrolimus when given to transplant recipients. Studies have shown, however, that the systemic absorption of tacrolimus when applied topically is very low, with blood concentrations being below the level of quantification in most patients. Moreover, TCIs are not associated with a decrease in immunocompetence in the skin and there is no increase in the incidence of infections with long-term treatment. More than 5.4 million prescriptions for tacrolimus ointment have been issued worldwide, with no evidence of an increased risk of malignancy in adults or children compared with the general population. Similarly, epidemiological studies have failed to demonstrate an increased incidence of skin cancer in patients using TCIs. The most common adverse events (AEs) that occur with tacrolimus ointment treatment are transient application-site reactions, such as burning or pruritus. These complications are related to disease severity, and decrease in frequency over time as AD improves. The incidence of nonapplication-site AEs does not increase with long-term treatment, and most such events occurring in clinical trials were considered to be unrelated to therapy. Although it is important that clinicians are aware of the recent changes in product labelling, extensive clinical trials continue to show that tacrolimus ointment is well tolerated, and is generally an effective therapy for suitable patients with AD.

Systemic ciclosporin and tacrolimus in dermatology

Ciclosporin and tacrolimus are calcineurin inhibiting immunosuppressant agents useful in the treatment of immune-mediated inflammatory dermatoses. Available data and clinical experience demonstrate ciclosporin's efficacy in treating psoriasis, atopic dermatitis, pyoderma gangrenosum, lichen planus, autoimmune bullous disease (in combination with corticosteroids), recalcitrant chronic idiopathic urticaria, and chronic dermatitis of the hands and feet. Although the role of topical tacrolimus in atopic dermatitis is well established, such experience with the oral formulation of tacrolimus has been limited. However, there are several case studies and anecdotal reports of the successful use of oral tacrolimus in various dermatoses. In this article we discuss the utility of systemic ciclosporin and tacrolimus in dermatology.

Oral graft vs. host disease in children – Treatment with topical tacrolimus ointment

Oral chronic graft vs. host disease (GVHD) frequently presents in patients with sclerotic features of skin GVHD and is often associated with considerable limitations of oral food intake and decreased quality of life. Systemic tacrolimus is efficacious for prophylaxis and treatment of acute and chronic GVHD and topical tacrolimus has shown activity in chronic GVHD skin lesions. We therefore initiated a pilot study to investigate the safety and efficacy of topical tacrolimus ointment in children with oral GVHD. Six patients suffering from oral GVHD (five chronic and one acute) were included in the study. Tacrolimus ointment 0.1% was applied twice daily using sterile gauze. The only side-effects observed were a slight burning discomfort after the first application in one patient and after food intake in another patient. Tacrolimus was absorbed systemically in four of six patients. Of six patients, we observed a complete response in two, a very good partial response (VGPR) in two, and a PR in two patients, respectively. We conclude that topical application of tacrolimus ointment holds promise as a safe and efficacious treatment for oral GVHD in children. The Food and Drug Administration has recently issued a health advisory about a potential cancer risk associated with topical tacrolimus treatment of the skin; therefore, its benefits should be weighed against its potential risks and diligent long-term follow-up should be carried out especially in children.

Efficacy and safety of inhaled tacrolimus in rat lung transplantation

Because acute rejection is the most important cause of chronic rejection in lung transplantation, the use of conventional systemic immunosuppression to improve long-term survival needs to be reassessed. The aim of this study was to investigate the efficacy and safety of inhaled tacrolimus for preventing acute rejection of rat lung allografts. Orthotopic left lung transplantation was performed in rats that were divided into 6 groups: control group received no treatment; groups 1.0-IM, 0.5-IM, and 0.3-IM received tacrolimus by intramuscular injection at 1.0, 0.5, and 0.3 mg/(kg.d), respectively; and groups 12-IT and 6-IT received 12 and 6 puffs of inhaled tacrolimus 3 times per day, respectively. Allografts were studied histologically. Whole blood and allograft tacrolimus concentrations were determined. In groups 1.0-IM and 12-IT, histologic grade of the graft showed significantly less rejection than in the other groups. The blood tacrolimus concentration in group 12-IT (4.87 ng/mL) was significantly lower than that in group 1.0-IM (13.05 ng/mL, P = .0017) on postoperative day 7. Higher allograft tacrolimus concentrations were achieved in group 1.0-IM (478.0 ng/g) than in group 12-IT (270.4 ng/g, P = .009). Weight loss and diarrhea in group 12-IT were less severe than in the groups that received systemic tacrolimus. The proliferating cell nuclear antigen index in bronchus-associated lymphoid tissue cells was significantly lower in group 12-IT than in group 1.0-IM (P = .0209). Local immunotherapy with inhaled tacrolimus has great potential for controlling pulmonary allograft rejection in clinical lung transplantation because it has fewer side effects than systemic immunosuppressive agents.