Recurrent rejections after liver transplantation for hepatocellular carcinoma with stem cell features in an adult patient.

Patients with hepatoblastoma featuring carcinoma characteristics have better outcomes after liver transplantation, than after chemotherapy and resection. Possibly this should be extrapolated to aggressive subtypes of hepatocellular carcinomas in non-cirrhotic livers, where early liver transplantation might also be indicated. However, the risks associated with liver transplantation and immunosuppressive treatment after liver transplantation are once again demonstrated by this case of a 32-year-old women with a negative personal and familial history of liver diseases. She underwent transplantation (DBD) for a hepatocellular carcinoma with stem cell features (HCC-HS; an aggressive 'hepatoblast subtype' of hepatocellular carcinoma) after chemotherapeutical downstaging techniques failed to sufficiently downstage the tumor. Despite being on conventional immunosuppressive regimens (tacrolimus and mycophenolate mofetil with initial corticosteroids tapered), this patient still developed two severe rejection episodes, one of which necessitated retransplantation (DCD). Both episodes were preceded by alterations in tacrolimus trough levels, either intentionally, when tacrolimus was reduced within a nephroprotective regimen, or unintentionally, when rifampicin, a CYP3A4 inducer, significantly lowered the trough levels. Together, these episodes stress the importance of therapeutic drug monitoring of tacrolimus. Furthermore, the patient experienced an everolimus-linked drug-induced thrombotic microangiopathy, underwent multiple ERCPs for an anastomotic stricture and only one and a half year after the first liver transplantation she already suffers from long-term immunosuppressive-related side effects such as impaired glucose tolerance, hypertension and a potential cardiomyopathy. At present, she is still alive and experienced no recurrence of her primary tumor. Her case underscores the significant challenges in post-liver transplantation care.

Tacrolimus-induced posterior reversible encephalopathy syndrome following liver transplantation.

In this editorial, we talk about a compelling case focusing on posterior reversible encephalopathy syndrome (PRES) as a complication in patients undergoing liver transplantation and treated with Tacrolimus. Tacrolimus (FK 506), derived from Streptomyces tsukubaensis, is a potent immunosuppressive macrolide. It inhibits T-cell transcription by binding to FK-binding protein, and is able to amplify glucocorticoid and progesterone effects. Tacrolimus effectively prevents allograft rejection in transplant patients but has adverse effects such as Tacrolimus-related PRES. PRES presents with various neurological symptoms alongside elevated blood pressure, and is primarily characterized by vasogenic edema on neuroimaging. While computed tomography detects initial lesions, magnetic resonance imaging, especially the Fluid-Attenuated Inversion Recovery sequence, is superior for diagnosing cortical and subcortical edema. Our discussion centers on the incidence of PRES in solid organ transplant recipients, which ranges between 0.5 to 5 +ACU-, with varying presentations, from seizures to visual disturbances. The case of a 66-year-old male status post liver transplantation highlights the diagnostic and management challenges associated with Tacrolimus-related PRES. Radiographically evident in the parietal and occipital lobes, PRES underlines the need for heightened vigilance among healthcare providers. This editorial emphasizes the importance of early recognition, accurate diagnosis, and effective management of PRES to optimize outcomes in liver transplant patients. The case further explores the balance between the efficacy of immunosuppression with Tacrolimus and its potential neurological risks, underlining the necessity for careful monitoring and intervention strategies in this patient population.

Cardiovascular toxicities by calcineurin inhibitors: Cellular mechanisms behind clinical manifestations.

Calcineurin inhibitors (CNI), including cyclosporine A (CsA) and tacrolimus (TAC), are cornerstones of immunosuppressive therapy in solid organ transplant recipients. While extensively recognized for their capacity to induce nephrotoxicity, hypertension, and dyslipidemia, emerging reports suggest potential direct cardiovascular toxicities associated with CNI. Evidence from both in vitro and in vivo studies has demonstrated direct cardiotoxic impact of CNI, manifesting itself as induction of cardiomyocyte apoptosis, enhanced oxidative stress, inflammatory cell infiltration, and cardiac fibrosis. CNI enhances cellular apoptosis through CaSR via activation of the p38 MAPK pathway and deactivation of the ERK pathway, and enhancement of miR-377 axis. Although CNI could attenuate cardiac hypertrophy in certain animal models, CNI concurrently impaired systolic function, enhanced cardiac fibrosis, and increased the risk of heart failure. Evidence from in vivo studies demonstrated that CNI prolong the duration of action potentials through a decrease in potassium current. CNI also exerted direct effects on endothelial cell injury, inducing apoptosis and enhancing oxidative stress. CNI may induce vascular inflammation through TLR4 via MyD88 and TRIF pathways. In addition, CNI affects vascular function by impairing endothelial-dependent vasodilation and promoting vasoconstriction. Clinical studies in transplant patients also revealed an increased incidence of cardiac remodeling. However, the evidence is constrained by the limited number of participants and potential confounding factors. Several studies indicate differing cardiovascular toxicity profiles between CsA and TAC, and these could be potentially due to their different interactions with calcineurin subunits and calcineurin-independent effects. Further studies are needed to clarify these mechanisms to improve cardiovascular outcomes for transplant patients with CNI.

Steroid-tacrolimus drug-drug interaction and the effect of CYP3A genotypes.

AIMS: Tacrolimus, metabolized by CYP3A4 and CYP3A5 enzymes, is susceptible to drug-drug interactions (DDI). Steroids induce CYP3A genes to increase tacrolimus clearance, but the effect is variable. We hypothesized that the extent of the steroid-tacrolimus DDI differs by CYP3A4/5 genotypes. METHODS: Kidney transplant recipients (n = 2462) were classified by the number of loss of function alleles (LOF) (CYP3A5*3, *6 and *7 and CYP3A4*22) and steroid use at each tacrolimus trough in the first 6 months post-transplant. A population pharmacokinetic analysis was performed by nonlinear mixed-effect modelling (NONMEM) and stepwise covariate modelling to define significant covariates affecting tacrolimus clearance. A stochastic simulation was performed and translated into a Shiny application with the mrgsolve and Shiny packages in R. RESULTS: Steroids were associated with modestly higher (3%-11.8%) tacrolimus clearance. Patients with 0-LOF alleles receiving steroids showed the greatest increase (11.8%) in clearance compared to no steroids, whereas those with 2-LOFs had a negligible increase (2.6%) in the presence of steroids. Steroid use increased tacrolimus clearance by 5% and 10.3% in patients with 1-LOF and 3/4-LOFs, respectively. CONCLUSIONS: Steroids increase the clearance of tacrolimus but vary slightly by CYP3A genotype. This is important in individuals of African ancestry who are more likely to carry no LOF alleles, may more commonly receive steroid treatment, and will need higher tacrolimus doses.

The use of extended-release tacrolimus twice a day might be beneficial for selected kidney transplant recipients: a case report.

The calcineurin inhibitor tacrolimus, which is available as an immediate- or extended-release formulation, is the standard-of-care immunosuppression after kidney transplantation with low rejection rates, especially in the first year after transplantation. However, its highly variable metabolism rate, narrow therapeutic window, and nephrotoxic side effects require close drug monitoring and individual dosing. Here, we describe first the application of extended-release tacrolimus (ER-Tac) twice daily with beneficial effects in a kidney transplant recipient under extensive therapeutic drug monitoring. A 47-year-old female kidney transplant recipient, who was identified as a fast metabolizer for tacrolimus, presented with declining allograft function and low tacrolimus through levels over time and 8 years after a second kidney transplantation despite the administration of high doses of ER-Tac once daily. Therefore, the area under the concentration-time curve (AUC) showed exceedingly high blood levels of ER-Tac. The latest biopsy of the kidney transplant showed arteriolar hyalinosis with pole vessel stenosis as a sign of chronic transplant vasculopathy and transplant glomerulopathy as a sign of chronic humoral rejection. After the exclusion of other options for immunosuppressive therapy due to the patient's high immunological risk, the patient was switched from ER-Tac once daily to ER-Tac twice daily. After switching to ER-Tac twice daily, the AUC for oral tacrolimus decreased and the transplant function improved despite higher tacrolimus trough levels and a lower total dose administered. This case highlights the importance of careful therapeutic drug monitoring with the performance of an AUC in the follow-up management of kidney transplant recipients.

Influence of ensitrelvir or nirmatrelvir/ritonavir on tacrolimus clearance in kidney transplant recipients: a single-center case series.

BACKGROUND: Among the oral antivirals used for treating patients with mild-to-moderate novel coronavirus disease 2019 (COVID-19), nirmatrelvir/ritonavir (NMV/RTV) and ensitrelvir (ESV) are inhibitors of cytochrome P450 (CYP) 3A, and therefore, can cause drug-drug interactions with concomitant medications. Tacrolimus (TAC), a substrate of CYP3A4/5, is administered for a long period to prevent rejection after kidney transplantation. TAC should be discontinued while using NMV/RTV because blood TAC levels significantly increase when these drugs are concomitantly administered. However, the influence of ESV on blood TAC levels has not yet been reported, and the management of TAC doses during the use of ESV remains unclear. CASE PRESENTATION: We experienced three kidney transplant recipients with COVID-19, whose blood trough levels of TAC increased by the concomitant use of NMV/RTV or ESV. In two patients administering NMV/RTV, blood trough levels of TAC increased more than tenfold after combination therapy, whereas in one patient administering ESV, TAC level increased approximately threefold. CONCLUSIONS: These cases suggest that TAC administration should be discontinued during NMV/RTV treatment to maintain blood TAC levels within the therapeutic range, and a reduced TAC dose is sufficient during ESV treatment.

Effect of early post-hematopoietic stem cell transplant tacrolimus concentration on transplant outcomes in pediatric recipients: One facility's ten-year experience of immunosuppression with tacrolimus.

Acute graft-versus-host disease (GVHD) is a common life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), ranking as the second leading cause of death among recipients, surpassed only by disease relapse. Tacrolimus is commonly used for GVHD prophylaxis, but achieving therapeutic blood levels is challenging, particularly in pediatrics, due to the narrow therapeutic window and the high interindividual variability. The retrospective study conducted at IRCCS "Burlo Garofolo" in Italy aimed to assess the impact of early post-HSCT tacrolimus levels on transplant-related outcomes in pediatric recipients. The population pharmacokinetic model (POP/PK) was set up to describe tacrolimus pharmacokinetics. Elevated tacrolimus (>12-15 ng/ml) levels within the initial weeks post-HSCT are associated with reduced post-transplant infections (p < 0.0001) and decreased incidence of early transplant-related events (p < 0.01), including a lower incidence of acute GVHD (p < 0.05 on day 0). High tacrolimus exposure can lead to an increased risk of chronic GVHD (p < 0.0001) and reduced overall survival (p < 0.01). Personalized dosing and therapeutic monitoring of tacrolimus are crucial to ensure optimal outcomes. POP/PK could help achieve this goal, giving us a model by which we can balance immunosuppression while looking at the patient's general well-being and providing the necessary treatment.

Rituximab versus tacrolimus as corticosteroid-sparing therapy for children with steroid-dependent nephrotic syndrome: A systematic review and meta-analysis of randomized and nonrandomized controlled trials.

Objectives: Prolonged use of corticosteroids induced complicated course in children with steroid-dependent nephrotic syndrome (SDNS), and the use of tacrolimus, a first-line alternative calcineurin inhibitor (CNI) agent was related to some unwanted adverse effects. Rituximab, a second alternative treatment has been proven to reliably reduce the number of relapses within 12 months with minimal adverse effects. Materials and Methods: Our review follows Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. All the databases were derived from MEDLINE, Proquest, EBSCOhost, Wiley, and Google Scholar within the past 11 years. The risk of bias was evaluated using the Revised Cochrane Risk of Bias Tool for Randomized Trials (RoB 2) and Risk of Bias in Non-Randomized Studies of Interventions. Meta-analysis used Review Manager (version 5.4) with a random effect model to obtain a pooled mean difference (MD) and odds ratio with 95% confidence intervals (CIs). Results: Four studies were included based on our eligibility criteria, and only three were included in the quantitative analysis. Three studies had low and one study had a moderate risk of bias. Pooled data results indicated that Rituximab was superior to tacrolimus in reducing the number of patients with 1-2 relapses (MD = 0.44, [95% CI: 0.21-0.91]) and had higher eGFR values (MD = 6.67; [CI - 2.92-10.61]). However, Rituximab showed insignificant superiority compared to tacrolimus in reducing the number of patients with 3 relapses, sustained remission, cumulative steroid use, serum cholesterol, and serum albumin concentrations. Conclusion: Rituximab exhibits more advantages in treating SDNS compared to tacrolimus, although the treatment options are highly individualized. Both regimens must also be weighed against their potential side effects to achieve a better overall health status.

Local FK506 delivery induces osteogenesis in rat bone defect and rabbit spine fusion models.

Bone grafting procedures are commonly used for the repair, regeneration, and fusion of bones in a wide range of orthopaedic surgeries, including large bone defects and spine fusion procedures. Autografts are the clinical gold standard, though recombinant human bone morphogenetic proteins (rhBMPs) are often used, particularly in difficult clinical situations. However, treatment with rhBMPs can have off-target effects and increase surgical costs, adding to patients' already high economic and mental burden. Recent studies have identified that FDA-approved immunosuppressant drug, FK506 (Tacrolimus), can also activate the BMP pathway by binding to its inhibitors. This study tested the hypothesis that FK506, as a standalone treatment, could induce osteogenic differentiation of human mesenchymal stromal cells (hMSCs), as well as functional bone formation in a rat segmental bone defect model and rabbit spinal fusion model. FK506 enhanced osteogenic differentiation and mineralization of hMSCs in vitro. Standalone treatment with FK506 delivered on a collagen sponge produced consistent bone bridging of a critically sized rat femoral defect with functional mechanical properties comparable to naïve bone. In a rabbit single level posterolateral spine fusion model, treatment with FK506 delivered on a collagen sponge successfully fused the L5-L6 vertebrae at rates comparable to rhBMP-2 treatment. These data demonstrate the ability of FK506 to induce bone formation in human cells and two challenging in vivo models, and indicate FK506 can be utilized to treat a variety of spine disorders.

Hemorrhagic events associated with tacrolimus: a real-world pharmacovigilance study.

BACKGROUND: Tacrolimus is a potent macrolide immunosuppressant frequently used to prevent graft rejection in organ transplantation. Despite the known side effect of hemorrhage, there are no extensive descriptive series of patients who experience hemorrhage events associated with tacrolimus. We sought to review and describe tacrolimus-related hemorrhage events reported by healthcare professionals to the United States Food and Drug Association Adverse Event Reporting System (FAERS) database. METHODS: The FAERS database (2004q1-2022q4) was retrospectively analyzed to characterize reporting of hemorrhage adverse events (AEs) with tacrolimus. Subgroup analysis was completed on the hemorrhage. RESULTS: A total of 75,310 tacrolimus-associated AEs were identified, of which 1,511 cases met specific inclusion/exclusion criteria with most occurring in the gastrointestinal tract (422 cases, 27.93% of all included cases). Death was reported in 558 patients (36.93% of hemorrhage cases), the most of which occurred in cases of brain hemorrhage (219 cases, 39.25% of death cases). Among definitive organ transplants, renal transplant was the most common indication for tacrolimus (62 cases, 4.10%) followed by bone marrow transplant (44 cases, 2.91%) and liver transplant (30 cases, 1.99%). CONCLUSIONS: This study presents the largest collective description of tacrolimus-related hemorrhage events. We additionally described a number of previously unreported tacrolimus-related hemorrhage events.

Topical Tacrolimus in Anterior Segment Disorders in Ophthalmology: A Review.

The purpose of this study is to emphasize topical tacrolimus's role in treating anterior segment diseases in ophthalmology. The present study analyzed research papers and publications from international databases, including Pubmed, MedLine, Google Scholar, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), and Scopus to highlight the significance and advantages of topical application of tacrolimus and its efficacy in treating allergic eye disorders, immune-mediated diseases, and other ocular surface disorders. Tacrolimus and cyclosporine are the two most commonly used topical immunosuppressants in ophthalmology. Tacrolimus is a selective calcineurin inhibitor administered for the prevention and treatment of allograft rejection in solid organ transplant recipients and has a similar mechanism of action to cyclosporine. Management of immune-mediated inflammatory anterior segment requires intense immunosuppression and studies have shown that tacrolimus is ten to hundred times more effective than cyclosporine. Abbreviations: IL-2 = interleukin-2, FDA = Food and Drug Administration Agency, GvHD = graft versus host disease, (Ig)E = immunoglobulin E, SAC = seasonal conjunctivitis, PAC = perennial allergic conjunctivitis, VKC = vernal keratoconjunctivitis, AKC = allergic keratoconjunctivitis, GPC = giant papillary conjunctivitis, PKC = phyctenular keratoconjunctivitis, DED = dry eye disease, TBUT = tear break up time.

An Adolescent Case of Anti-MDA5 Antibody-Positive Juvenile Dermatomyositis With Interstitial Lung Disease Successfully Treated by Multitarget Therapy Avoiding Cyclophosphamide: A Case Report and Literature Review.

Juvenile dermatomyositis (JDM) patients who test positive for the antimelanoma differentiation-associated gene 5 (MDA5) antibody have a poor prognosis because of rapidly progressing interstitial lung disease (ILD). However, agreement on the best treatment for this condition remains elusive. We encountered a 13-year-old girl with anti-MDA5 antibody-positive JDM who presented with arthritis and was already showing signs of ILD when she was admitted to the hospital. While cyclophosphamide (CY) is commonly used, it can cause gonadal disorders and other complications when administered to adolescent females. Consequently, we chose multitarget therapy, which includes tacrolimus and mycophenolate mofetil. Her ILD and skin symptoms gradually improved, and she was able to maintain remission and avoid CY administration for three years. We conducted a thorough literature review to determine the efficacy and safety of multitarget therapy for anti-MDA5 antibody-positive DM and JDM. Multitarget therapy shows promise as a potentially effective and relatively safe treatment. The ability to avoid CY, which is especially important for adolescent patients concerned about fertility preservation, highlights a significant benefit of this multitarget therapy for anti-MDA5 antibody-positive DM and JDM patients.

Hydroxychloroquine-induced generalized myopathy in a patient with lupus tumidus: a case report.

A subtype of cutaneous lupus erythematosus known as lupus erythematosus tumidus (LET) is characterized by sun-exposed areas that typically display urticaria-like papules and plaques. For LET, systemic therapy with antimalarials - particularly hydroxychloroquine (HCQ) - is the first line of treatment. Even though the safety profile of these medications appears to be high, there have been very few reports of side effects in the literature, including hemolytic anemia, retinal toxicity, maculopapular rash, gastrointestinal disturbance, and blue-gray discoloration of the skin or mucous membranes. Here, we report a unique instance of a 46-year-old LET smoker who, following HCQ treatment, developed a generalized myopathy.

Treatment with low-dose nintedanib and tacrolimus in patients with progressive fibrosing interstitial lung diseases with anti-ARS antibody-positive dermatomyositis.

Nintedanib has been demonstrated to inhibit the rate of forced vital capacity decline in patients with progressive fibrosing interstitial lung diseases (PF-ILD) at a dose of 200 or 300 mg/day in the INBUILD trial. Although concomitant use of nintedanib with P-glycoprotein inhibitors reportedly increases the plasma concentrations of the former, tacrolimus, a P-glycoprotein inhibitor, is often used to treat connective tissue diseases-related interstitial lung diseases. The optimal dose of nintedanib in combination with tacrolimus for the treatment of PF-ILD with connective tissue disease is unknown. We herein present two patients with PF-ILD with anti-aminoacyl-tRNA synthetase antibody-positive dermatomyositis who were successfully treated with low-dose nintedanib (<200 mg/day) in combination with tacrolimus.

Belatacept-based immunosuppression does not confer increased risk of BK polyomavirus-DNAemia relative to tacrolimus-based immunosuppression.

BACKGROUND: The effect of belatacept on BK polyomavirus (BKPyV) control remains largely unknown. METHODS: This is a propensity matched retrospective cohort study in adult kidney transplant recipients (KTR) transplanted between 2016-2020 who received a belatacept- versus tacrolimus-based immunosuppression regimen. A continuous time multi-state Markov model was used to evaluate BKPyV replication dynamics (BKPyV-dyn). Three BKPyV-dyn states were defined: BKPyV-dyn1 (viral load <3 log10), BKPyV-dyn2 (viral load ≥ 3 log10 and ≤4 log10), and BKPyV-dyn3 (viral load >4 log10). RESULTS: Two hundred eighty KTR on belatacept- and 280 KTR on tacrolimus-based regimens were compared. The probability of transitioning between BKPyV-dyn states and time spent in each state in both groups was comparable. Total duration in BKPyV-dyn-1 was 632.1 days (95% CI 612.1, 648.5) for belatacept versus 615.2 days (95% CI 592.5, 635.8) for tacrolimus, BKPyV-dyn-2 was 49.2 days (95% CI 41.3, 58.4) for belatacept versus 55.6 days (95% CI 46.5, 66.8) for tacrolimus, and BKPyV-dyn-3 was 48.7 days (95% CI 37.1, 363.1) for belatacept versus 59.2 days (95% CI 45.8, 73.5) for tacrolimus. BKPyV associated nephropathy (PyVAN) occurred in 3.9% in belatacept- and 3.9% tacrolimus-treated KRT (P > .9). CONCLUSIONS: Compared with tacrolimus-based immunosuppression, belatacept based immunosuppression was not associated with increased risk of BKPyV-DNAemia or nephropathy.

Case report and literature review: management of Paxlovid (nirmatrelvir/ritonavir)-induced acute tacrolimus toxicity in a patient with systemic lupus erythematosus.

Despite the availability of effective vaccines and treatments for SARS-CoV-2, managing COVID-19 in patients with systemic lupus erythematosus (SLE) remains challenging, particularly considering drug-drug interactions (DDIs). Here, we present a case of DDIs between Tacrolimus (Tac) and nirmatrelvir/ritonavir (NMV/r) in a 32-year-old male with SLE. Following self-administration of NMV/r and resumption of Tac after 5 days, the patient experienced acute nephrotoxicity and neurotoxicity, accompanied by supratherapeutic Tac levels, despite Tac being withheld during NMV/r. The primary cause of this acute toxicity is attributed to ritonavir's inhibitory effect on both CYP3A4 enzymes and P-glycoprotein. Upon admission, Tac was discontinued, and supportive therapies were initiated. Phenytoin, a CYP3A4 inducer, was administered to lower Tac levels under the guidance of clinical pharmacists, effectively alleviating the patient's acute toxic symptoms. The half-life of Tac during the treatment of phenytoin was calculated to be 55.87 h. And no adverse reactions to phenytoin were observed. This case underscores the persistence of enzyme inhibition effects and demonstrates the effectiveness and safety of utilizing CYP3A4 enzyme inducers to mitigate Tac concentrations. Furthermore, it emphasizes the importance of healthcare providers and patients being vigilant about DDIs in Tac recipients. Lastly, it highlights the indispensable role of pharmacist involvement in clinical decision-making and close monitoring in complex clinical scenarios. Although our findings are based on a single case, they align with current knowledge and suggest the potential of individualized combination therapy in managing challenging COVID-19 cases in immunocompromised patients.

Flexible microneedles incorporating gold nanorods and tacrolimus for effective synergistic photothermal-chemotherapy of rheumatoid arthritis.

Transdermal drug delivery systems for rheumatoid arthritis (RA) have garnered substantial attention due to their great potential to overcome limitations observed in conventional oral or injection strategies, including limited selectivity and adverse effects on extra-articular tissues. Microneedles (MNs) appear to be highly desirable carriers for transdermal drug delivery of RA. However, microneedles typically are unable to keep up with the flexibility of joints, which decreases the effectiveness of administration. In this study, we developed a flexible microneedles (FMNs) delivery system. And gelatin was employed for the fabrication of flexible backings for microneedles owing to its excellent ductility and biocompatibility. We achieved synergisticphotothermal-chemotherapy of RA by incorporating the chemical drug Tacrolimus (TAC) and the photothermal agent gold nanorods (AuNRs) into dissolving microneedles. Results showed a high mechanical strength of the proposed FMNs. In the animal model of adjuvant-induced arthritis (AA), it is indicated that the prepared FMNs inhibited the expression of related inflammatory cytokines such as IL-1ß and TNF-α while enhancing bone repair and other related factors. Thus, the combination therapy of FMNs-mediated hyperthermia and chemotherapy can serve as a novel and synergistic treatment option for RA.

Removing the physician from the equation: Patient-controlled, home-based therapeutic drug self-monitoring of tacrolimus.

The dosing of tacrolimus, which forms the backbone of immunosuppressive therapy after kidney transplantation, is complex. This is due to its variable pharmacokinetics (both between and within individual patients), narrow therapeutic index, and the severe consequences of over- and underexposure, which may cause toxicity and rejection, respectively. Tacrolimus is, therefore, routinely dosed by means of therapeutic drug monitoring (TDM). TDM is performed for as long as the transplant functions and frequent and often lifelong sampling is therefore the rule. This puts a significant burden on patients and transplant professionals and is associated with high healthcare-associated costs. Furthermore, by its very nature, TDM is reactive and has no predictive power. Finally, the current practice of TDM does not foresee in an active role for patients themselves. Rather, the physician or pharmacist prescribes the next tacrolimus dose after obtaining the concentration measurement test results. In this article, we propose a strategy of patient-controlled, home-based, self-TDM of the immunosuppressant tacrolimus after transplantation. We argue that with the combined use of population tacrolimus pharmacokinetic models, home-based sampling by means of dried blood spotting and implementation of telemedicine, this may become a feasible approach in the near future.

Efficacy of tacrolimus monotherapy in primary membranous nephropathy.

Objective: The aim of this study was to observe the remission of primary membranous nephropathy (PMN) and evaluate the efficacy of tacrolimus (TAC) monotherapy for PMN in comparison with TAC combined with a low-dose glucocorticoid (GC) protocol (TAC + GC). Methods: This was tested in a prospective monocentric observational trial of 70 patients with PMN, of whom 34 received TAC (0.05-0.075 mg/kg/day) or 36 received TAC (0.05-0.075 mg/kg/day) and GC (0.3-0.5 mg/kg/day of prednisone). Results: At 3, 6, 9, and 12 months of treatment, the effective rates in the TAC group and the TAC + GC group were similar (P > 0.05). The urinary protein quantification was reduced in patients under both therapeutic protocols, and the differences in the proteinuria quantification at 3, 6, 9, and 12 months of treatment were not statistically significant between the two groups (P > 0.05). The overall incidence of adverse reactions in the TAC group was lower than that in the TAC + GC group (23.5% < 36.1%), and the difference was statistically significant (P < 0.05). Conclusion: TAC monotherapy for PMN could effectively reduce urinary protein quantification and increase serum albumin levels. Compared with TAC + GC, TAC monotherapy for PMN had no difference in efficacy and fewer incidences of adverse reactions.

Comparative Study Between Tacrolimus 0.1% Ointment Versus Topical White Soft Petrolatum Jelly in the Treatment of Oral Retinoid-Induced Cheilitis.

Retinoids are used topically as well as orally, and the most commonly used oral retinoids are isotretinoin and acitretin. Mucocutaneous adverse effects are frequently seen with the use of systemic retinoids, the most common being cheilitis, which is dose-dependent and seen in almost all patients using it. To study the comparative effect of topical tacrolimus 0.1% ointment versus topical white soft petrolatum jelly in the treatment of cheilitis due to retinoids. A total of 26 patients with cheilitis post-treatment with isotretinoin were enrolled in this cross-sectional study conducted over a period of 6 months. They were randomized into two groups of 13 patients each to receive topical tacrolimus 0.1% ointment and soft petrolatum jelly twice daily, respectively. Patients were followed up weekly with clinical photographs. Resolution of cheilitis was assessed on the basis of photograph and ICGS score. About 84.6% of patients of group A and 53.8% of patients of group B showed resolution of symptoms within 1 week of treatment. A significant difference was seen in duration for complete cheilitis resolution and relapse rate in the two groups. Our study concludes that oral retinoid-induced cheilitis shows faster and more significant resolution with twice-daily topical tacrolimus 0.1% ointment application compared to twice-daily topical petrolatum jelly.