Background/Objectives: Liver diseases and chronic inflammatory bowel diseases (IBD) are closely associated, particularly primary sclerosing cholangitis (PSC) and ulcerative colitis (UC). In severe cases of PSC, liver transplantation (LT) may be required, just as severe IBD may necessitate biologic therapy. Evidence on combining biologics with post-transplant immunosuppression is limited, particularly regarding hepatotoxicity, infections, and drug-drug interactions. We therefore assessed the safety of biologic therapy for IBD in LT recipients. Methods: In this retrospective, single-center analysis, all patients treated at the inflammatory bowel disease and post-liver transplantation outpatient clinics of the University Hospital Regensburg were screened. Patients with both LT and IBD were included in the analysis. Medical records, laboratory parameters, and imaging studies were reviewed. Conclusions: A total of 17 liver transplant recipients with IBD were identified. Eleven patients had PSC as the underlying liver disease, while the remaining patients had autoimmune hepatitis (AIH), PSC-AIH overlap syndrome, or cryptogenic liver cirrhosis. Three patients had Crohn's disease, and 14 had ulcerative colitis. Five patients required biologic therapy because of active IBD. Two patients received two sequential biologic agents, whereas one patient received four different biologics during follow-up. No significant safety signals were observed regarding hepatotoxicity, susceptibility to infections, or interactions with concomitant immunosuppressive therapy, including tacrolimus, mycophenolate mofetil, ciclosporin, and prednisolone. No evidence of clinically relevant safety concerns associated with biologic therapy was identified in liver transplant recipients with IBD. Therefore, biologic therapy combined with conventional post-transplant immunosuppression appears feasible and well tolerated in LT recipients with active IBD; larger prospective studies are needed. However, larger prospective studies are needed to confirm these findings.

Background/Objectives: Long-term immunosuppressive therapy administered to solid organ transplant recipients may induce adverse effects in various tissues, including the gastrointestinal tract. The aim of the present study was to evaluate the influence of prolonged treatment with calcineurin inhibitor (CNI)-based triple immunosuppressive regimens on the morphology of the jejunal mucosa in male rats. Particular attention was paid to fibrotic changes occurring within the mucosal connective tissue, including the intestinal villi and lamina propria. Methods: Animals were treated for six months with regimens containing either cyclosporine A (CyA) or tacrolimus (TAC) in combination with rapamycin and prednisone. To assess the content of collagen fibers, jejunal sections were stained using the Mallory trichrome method and subsequently subjected to quantitative digital image analysis. Results: Histological examination demonstrated increased collagen deposition in the jejunal mucosa of rats receiving immunosuppressive treatment compared with the control group. Quantitative analysis confirmed an increase in collagen fiber content, indicating enhanced extracellular matrix accumulation and changes consistent with fibrotic remodeling of the mucosal connective tissue. The highest collagen fiber content was observed in animals treated with the cyclosporine-based regimen. Conclusions: These findings suggest that long-term administration of CNI-based triple immunosuppressive therapy may be associated with changes consistent with fibrotic remodeling of the jejunal mucosa. The present study provides novel data on the effects of clinically relevant multidrug immunosuppressive protocols, whereas most previous experimental studies investigating the effects of immunosuppressive agents have focused on single-drug exposure in animal models or in vitro systems.

Tacrolimus is a potent calcineurin inhibitor suitable for the local treatment of oral mucosal immune-mediated diseases; however, no buccal formulation is currently available. The main objective of this work was to develop a mucoadhesive, semi-solid formulation containing tacrolimus that has adequate mucoadhesion salivation, and effective mucosal penetration with low systemic availability. A series of tacrolimus containing semisolid formulations based on chitosan, carbomer and hypromellose (HPMC) as mucoadhesive polymers were developed. Their rheologic behavior, pH value, macroscopic and microscopic properties as well as mucoadhesion and mucosal penetration were investigated. Lactate buffer was successfully used to stabilize chitosan against hydrolysis. It was shown that diols of different chain length, like 1,2-propanediol 1,2-pentanediol and 1,2-hexanediol improved mucosal penetration but reduced mucoadhesion due to gel matrix weakening. After 60 min in the mucoadhesion cell, mucosal tacrolimus amounts versus salivary wash-off for the diols were 0.78 ± 0.09 µg/cm[2] versus 0.47 ± 0.20% for 20% 1,2-propanediol, 1.99 ± 0.23 µg/cm[2] versus 14.26 ± 3.01% for 40% 1,2-propanediol, 3.56 ± 0.29 µg/cm[2] versus 25.04 ± 1.68% for 20% 1,2-pentanediol, and 3.66 ± 0.25 µg/cm[2] versus 28.13 ± 4.00% for 20% 1,2-hexanediol. A series of tacrolimus formulations with different degrees of mucoadhesion, salivary retention and penetration characteristics was successfully developed.

Pediatric-onset ulcerative colitis (UC) is characterized by an aggressive phenotype, with higher rates of pancolitis and more rapid progression to a medically refractory state. After failure of conventional therapies and multiple biologic agents, treatment options are limited and often require surgery. We report the case of a 15-year-old girl with a 5-year history of highly refractory pancolitis-type UC. Previous treatments included mesalazine, salazosulfapyridine, tacrolimus, and three biologic agents (infliximab, vedolizumab, and adalimumab), all of which failed to maintain remission. After ustekinumab initiation, she initially experienced mild improvement but subsequently developed a severe clinical relapse (Pediatric Ulcerative Colitis Activity Index score: 40-50) triggered by Edwardsiella tarda infection. Despite infection resolution and treatment with systemic corticosteroids, her condition remained critical. As adjunctive therapy, intensive granulocyte and monocyte adsorptive apheresis (GMA) was administered twice weekly for 10 sessions, followed by twice monthly for 7 sessions, resulting in rapid symptomatic improvement. Follow-up colonoscopy confirmed complete mucosal healing (Mayo Endoscopic Subscore, 0). Intensive GMA may be a safe and effective adjunct to ustekinumab before its full therapeutic effect is achieved, potentially complementing the anti-inflammatory effects of ustekinumab in refractory pediatric UC and may help avoid colectomy even when multiple drug therapies have failed.

Physiologically based pharmacokinetic (PBPK) models are increasingly used in pediatric drug development and matching such models to the target population is an important consideration. A US pediatric PBPK model was developed incorporating four sub-groups describing physiology and enzymatic/transporter levels for White, African American, Hispanic/Latino and Asian subjects. Virtual populations could then be created reflecting the demographics of the clinical study design. Ten different drugs (14 studies) were used to verify the pediatric PBPK model performance. Predicted PK parameters showed reasonable agreement with observed data, 50% of the predicted: observed values were within 0.8-1.25-fold, 74% within 0.67-1.5-fold, and 97% within 0.5-2-fold. There was minimal difference for most drugs in performance between the mixed US and North European pediatric populations. This was partly due to reported studies having low numbers of subjects and under-representation of some ethnicities. Power calculations showed that to detect a pharmacokinetic difference for the CYP3A4/5 substrates midazolam, sirolimus and tacrolimus between African American and White American children with a power of 80%, 25, 18 and 12 subjects respectively, in each group would be needed. Developing adult and pediatric PBPK models to closely match study populations is important due to their increased regulatory use and with the move to their application in personalized medicine. Such models may also help to bridge some of the ethnic differences not captured in pediatric clinical studies due to the low numbers of subjects.

While heart transplantation (HT) is the optimal therapy for end-stage heart failure patients, longevity of HT recipients continues to be limited by rejection and its sequelae. In this review, we provide an overview of current immunosuppressive principles and the prevention, diagnosis and treatment of rejection in HT. All HT recipients are maintained on immunosuppression to prevent rejection and undergo regular surveillance testing to identify rejection episodes that may require treatment. Risk of rejection is highest in the first year-post-HT and so during that period, immunosuppression is maintained at the highest levels and surveillance testing is done most frequently. The current standard triple-drug immunosuppressive regimen for HT consists of tacrolimus, a calcineurin inhibitor, mycophenolate mofetil, an antimetabolite agent and steroids. This regimen, with a calcineurin inhibitor as its cornerstone, has led to significantly decreased rates of rejection, particularly acute cellular rejection (ACR) in the current day compared with the early days of HT. The endomyocardial biopsy is currently the standard for rejection surveillance, but newer technologies such as donor-derived cell-free DNA measurements are changing surveillance practices in the field. While rates of ACR have decreased with current management strategies, antibody-mediated rejection (AMR) continues to pose a challenge. Newer immunosuppressive therapies that more effectively target the humoral and innate immune systems aim to better prevent and treat AMR in HT recipients. Furthermore, ongoing advancements in rejection surveillance strategy offer higher sensitivity and diagnostic accuracy for AMR compared with just histopathology on the endomyocardial biopsy. Ongoing advancements in immunosuppression and rejection surveillance will lead to continued improvement in longevity of HT recipients.