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Copyright of Polish Nephrology & Dialyzotherapy / Nefrologia i Dializoterapia Polska is the property of Wydawnictwo Przegld Lekarski / Publisher Medicine Review and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Systemic calcineurin inhibitors, cyclosporine, tacrolimus, and voclosporin, have been utilized in various dermatologic conditions. Although there have been numerous off-label dermatologic indications with published guidelines for cyclosporine, there is no established strong consensus for tacrolimus and voclosporin. To conduct a review of off-label use of systemic tacrolimus and voclosporin in various dermatoses to better inform treatment methods. A literature search was conducted using PubMed and Google Scholar. Relevant clinical trials, observational studies, case series, and reports regarding off-label dermatologic uses of systemic tacrolimus and voclosporin were included. Tacrolimus shows promise for numerous dermatologic conditions, including psoriasis, atopic dermatitis/eczema, pyoderma gangrenosum, chronic urticaria, and Behcet's disease. Randomized controlled trial data are only available for voclosporin in psoriasis, which showed efficacy but did not meet noninferiority to cyclosporine. Data were limited and extracted from published papers. Studies differed in methodology, and nonstandardized outcomes limited the conclusions drawn. In comparison to cyclosporine, tacrolimus can be considered for treatment-refractory disease or in patients with cardiovascular risk factors or inflammatory bowel disease. Voclosporin has only been utilized in psoriasis currently, and clinical trials in psoriasis show voclosporin's efficacy. Voclosporin can be considered for patients with lupus nephritis. [ABSTRACT FROM AUTHOR]

Resumen: La nefritis lúpica (NL) es una manifestación grave del lupus eritematoso sistémico que puede llevar a una enfermedad renal terminal. La mayor parte de los datos clínicos y pronósticos que manejamos, y sobre los que tomamos decisiones terapéuticas, proceden de cohortes internacionales con importantes diferencias étnicas y relativas al pronóstico renal. Para conocer los datos clínicos y pronósticos de los pacientes con NL en España se realizó una búsqueda bibliográfica de artículos relacionados con la NL publicados por autores españoles en revistas nacionales e internacionales entre 2005 y 2022. Las referencias seleccionadas mostraron que la biopsia no solo es clave en el diagnóstico de la NL, sino que su repetición puede ser útil en el seguimiento. En cuanto al tratamiento el abordaje estándar de la NL consiste en una fase de inducción y una fase de mantenimiento. Sin embargo, la aparición de nuevos fármacos ha motivado que se postule un nuevo paradigma de tratamiento en una sola fase continuada y personalizada. Abstract: Lupus nephritis (LN) is a serious manifestation of systemic lupus erythematosus that can lead to end-stage renal disease. Many clinical and prognostic data on which our therapeutic decisions are based come from international cohorts, which have important ethnic and prognostic differences. To identify clinical and prognostic data from patients with LN in Spain, we undertook a bibliographic search of LN-related papers by Spanish authors and published in national and international journals between 2005 and 2022. According to the selected references, renal biopsy is not only essential for LN diagnosis but its repetition can be useful for the follow-up. Regarding LN treatment, standard strategy consists of an induction phase and a maintenance phase. However, as new drugs have been released, a new paradigm of treatment in a single, continuing and personalized phase has been proposed.

Objective: This study was to assess the safety and effectiveness of immunosuppressive agents, specifically Voclosporin, when used in conjunction with mycophenolate mofetil (MMF) induction therapy for the management of lupus nephritis (LN). Methods: A systematic review and network meta-analysis (NMA) was conducted on randomized controlled trials investigating the efficacy of immunosuppressant-induced therapy for LN. The random effects model was used in the analysis. I² was used to evaluate the heterogeneity of the model. Odds ratios (OR) and 95% credible intervals (CrI) were computed to assess and compare the relative effectiveness and safety of various treatment protocols. Results: The study included a total of 16 randomized controlled trials (RCTs) involving 2444 patients with LN. The analysis results indicated that there was no significant difference in terms of partial remission (PR) between the drugs. However, when considering complete remission (CR), the combination of Voclosporin with MMF showed the highest remission rate, followed by Tacrolimus (TAC). Unfortunately, Voclosporin in combination with MMF had the highest risk of infection and serious infection, indicating a lower safety profile. Conclusions: Voclosporin in combination with MMF demonstrated the highest efficacy as an induction therapy for LN. However, it should be noted that the risk of infection and serious infection was found to be high with this regimen. On the other hand, TAC not only showed efficacy but also had a lower risk of infection and serious infection, making it a favorable option in terms of safety. This study did' not include results on other adverse events. [ABSTRACT FROM AUTHOR]

Copyright of Nefrologia is the property of Revista Nefrologia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Childhood-onset systemic lupus erythematosus is an inflammatory and autoimmune condition characterized by heterogeneous multisystem involvement and a chronic course with unpredictable flares. Kidney involvement, commonly called lupus nephritis, mainly presents with immune complex-mediated glomerulonephritis and is more frequent and severe in adults. Despite a considerable improvement in long-term renal prognosis, children and adolescents with lupus nephritis still experience significant morbidity and mortality. Moreover, current literature often lacks pediatric-specific data, leading clinicians to rely exclusively on adult therapeutic approaches. This review aims to describe pediatric lupus nephritis and provide an overview of the novel perspectives on the pathogenetic mechanisms, histopathological classification, therapeutic approach, novel biomarkers, and follow-up targets in children and adolescents with lupus nephritis. [ABSTRACT FROM AUTHOR]

Copyright of Zeitschrift für Rheumatologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Cyclosporine is a valuable drug in the dermatologic spectrum. It is of particular value when an immediate outcome is desired. However, owing to its toxicity profile, it cannot be used for a prolonged period, thereby making it predominantly a crisis-buster drug. This review will throw light on all the essentials of cyclosporine that would be mandatory for any practicing dermatologist. [ABSTRACT FROM AUTHOR]

Background and aimsAcute severe steroid-refractory ulcerative colitis remains a medically challenging condition with frequent need of surgery. It can be treated with the calcineurin inhibitor cyclosporine A with the need for therapeutic drug monitoring and significant toxicity. Recently, a novel calcineurin inhibitor, voclosporin, has been approved for the treatment of lupus nephritis with no need for therapeutic drug monitoring and an improved long-term safety profile. However, the therapeutic effect of voclosporin in acute severe steroid-refractory ulcerative colitis is still uncertain. We aimed to assess the therapeutic potential of voclosporin to ameliorate inflammation in an experimental model of colitis.MethodsWe used the dextran sodium sulfate-induced model of colitis in C57BL/6 J wildtype mice treated with either cyclosporine A, voclosporin or solvent control. We employed endoscopy, histochemistry, immunofluorescence, bead-based multiplex immunoassays and flow cytometry to study the therapeutic effect of calcineurin inhibitors in a preventive setting.ResultsAcute colitis was induced by dextran sodium sulfate characterized by weight loss, diarrhea, mucosal erosions and rectal bleeding. Both cyclosporine A and voclosporin strongly ameliorated the course of disease and reduced colitis severity in a similar manner.ConclusionVoclosporin was identified as biologically effective in a preclinical model of colitis and may be a potential therapeutic option in treating acute severe steroid-refractory ulcerative colitis.

Voclosporin is a potent immunosuppressive agent currently approved for treating active lupus nephritis. Based on its potential antiviral activity, it has also been investigated as immunosuppressive agent in an investigator-initiated study in SARS-CoV2 positive kidney transplant recipients. As with many immunosuppressive agents, optimizing dosing regimens to achieve therapeutic efficacy while minimizing toxicity remains a critical challenge in clinical practice. To prevent organ rejection as well as infections, the prescribed immunosuppression needs to be well balanced. Dried blood spot (DBS) sampling has enabled development of remote voclosporin therapeutic drug monitoring. Here, we report on the development and analytical validation of a liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for quantification of voclosporin in dried blood spots. Method development was based on previously developed assays for the quantification of tacrolimus, everolimus, sirolimus, cyclosporin, mycophenolic acid, creatinine and iohexol in DBS and voclosporin in whole blood using LC-MS/MS. HemaXis™ volumetric blood spot devices were used for sample collection. The sample purification was based on the extraction of voclosporin from the DBS samples. Stable isotopically labeled voclosporin-D4 was used as an internal standard prior to sample purification. Bland Altman and Passing bablok analysis were performed for cross validation between whole blood and DBS samples. The method was successfully validated following the current ICH M10 guidelines. The dynamic range for the analyte was 10-600 µg/L with an excellent mean coefficient of correlation of 0.9978. The within run and between run precision and accuracy were both within the acceptance criteria. The cross-validation against the whole blood method shows that the quantified voclosporin results are promising. This developed dried blood spot LC-MS/MS method was successfully validated and provides an easy, efficient workflow for therapeutic drug monitoring in kidney transplant patients or remote pharmacokinetic studies in lupus nephritis patients treated with voclosporin., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Y.K.O. Teng reports financial support and equipment, drugs, or supplies were provided by Aurinia Pharmaceuticals Inc. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Negative food effect refers to a reduction in bioavailability, when a drug is taken with food. Voclosporin, a highly lipophilic cyclic peptide drug for treatment of active lupus nephritis, has shown negative food effect in clinical trials. Here, the cause of the negative food effect of voclosporin was investigated using physiologically based pharmacokinetic (PBPK) modeling to understand the mechanism responsible for oral absorption of voclosporin. Voclosporin is a substrate for P-glycoprotein and CYP3A4, and it has been evaluated for intestinal membrane permeability in human induced pluripotent stem cell-derived intestinal epithelial cells (hiPSC-IECs). The membrane permeability in hiPSC-IECs is integrated into the PBPK model for simulating permeability accurately. The PBPK model simulated the systemic PK profile in fasted state in human. Then, the PBPK model with in vitro adsorption of voclosporin onto food simulated the systemic PK profile in fed state for food effect. In addition, the PBPK model for rats also simulated the plasma profile of voclosporin for the food effect. These results suggest that a possible cause of the negative food effect of voclosporin is the adsorption of voclosporin to food in gastrointestinal tract. These approaches could facilitate understanding of the mechanisms responsible for oral absorption of cyclic peptides., Competing Interests: Declaration of competing interest Watanabe, Akazawa and Fujiu are employees of Shionogi & Co., Ltd., (Copyright © 2024 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Childhood-onset systemic lupus erythematosus is an inflammatory and autoimmune condition characterized by heterogeneous multisystem involvement and a chronic course with unpredictable flares. Kidney involvement, commonly called lupus nephritis, mainly presents with immune complex-mediated glomerulonephritis and is more frequent and severe in adults. Despite a considerable improvement in long-term renal prognosis, children and adolescents with lupus nephritis still experience significant morbidity and mortality. Moreover, current literature often lacks pediatric-specific data, leading clinicians to rely exclusively on adult therapeutic approaches. This review aims to describe pediatric lupus nephritis and provide an overview of the novel perspectives on the pathogenetic mechanisms, histopathological classification, therapeutic approach, novel biomarkers, and follow-up targets in children and adolescents with lupus nephritis.

Aim: The safety of multitarget treatments is of concern. This study aimed to evaluate the effectiveness and safety of multitarget therapy as an induction treatment for lupus nephritis in comparison with monotherapy. Methods: This study included randomized controlled trials (RCTs) that evaluated the effectiveness and safety of multitarget therapies, such as voclosporin+mycophenolate mofetil (MMF), tacrolimus+MMF, or belimumab+standard of care in comparison with MMF or cyclophosphamide (CYC) monotherapy for induction treatment of lupus nephritis. We performed a meta-analysis of the efficacy and safety of multitarget therapy as an induction treatment for lupus nephritis in comparison with monotherapy Results: Six RCTs, including 1,437 participants, met the inclusion criteria. The complete remission rate was significantly higher in the multitarget therapy group than in the monotherapy group (odds ratio, 2.155; 95% CI, 1.695–2.739; p < 0.001). Subgroup analysis revealed that the complete remission rate was significantly higher in both tacrolimus+MMF and voclosporin+MMF groups as well as the belimumab+standard of care (SOC) than in the monotherapy or SOC group. The incidence of adverse events did not differ between the multitarget therapy and monotherapy groups. However, cases of infection and pneumonia were numerically higher in the multitarget therapy group than in the monotherapy group. In addition, the incidence of menstrual disorder was significantly lower in the tacrolimus+MMF group than in the CYC group, whereas that of new-onset hypertension was considerably higher in the tacrolimus+MMF group than in the CYC group. Conclusions: Multitarget therapy showed a higher complete remission rate than monotherapy; however, cases of infection and pneumonia were numerically more elevated in the multitarget therapy group than in the monotherapy group. [ABSTRACT FROM AUTHOR]

Kidney transplant recipients (KTRs) are at increased risk for a more severe course of COVID-19, due to their pre-existing comorbidity and immunosuppression. Consensus protocols recommend lowering immunosuppression in KTRs with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the optimal combination remains unclear. Calcineurin inhibitors (CNIs) are cornerstone immunosuppressants used in KTRs and some have been reported to possess antiviral activity against RNA viruses, including coronaviruses. Here, we evaluated the effect of the CNIs tacrolimus, cyclosporin A, and voclosporin (VCS), as well as other immunosuppressants, on SARS-CoV-2 replication in cell-based assays. Unexpected, loss of compound due to plastic binding and interference of excipients in pharmaceutical formulations (false-positive results) complicated the determination of EC50 values of cyclophilin-dependent CNI’s in our antiviral assays. Some issues could be circumvented by using exclusively glass lab ware with pure compounds. In these experiments, VCS reduced viral progeny yields in human Calu-3 cells at low micromolar concentrations and did so more effectively than cyclosporin A, tacrolimus or other immunosuppressants. Although, we cannot recommend a particular immunosuppressive regimen in KTRs with COVID-19, our data suggest a potential benefit of cyclophilin-dependent CNIs, in particular VCS in reducing viral progeny, which warrants further clinical evaluation in SARS-CoV-2-infected KTRs. [ABSTRACT FROM AUTHOR]

Background An open-label phase 1 study was conducted to evaluate the effect of voclosporin following dosing with mycophenolate mofetil (MMF) on blood levels of mycophenolic acid (MPA, the active moiety of MMF) and MPA glucuronide (MPAG, the pharmacologically inactive metabolite of MMF) in subjects with systemic lupus erythematosus (SLE) and to assess the safety and tolerability of the combination. Methods MMF was orally administered at a dose of 1 g twice a day for at least 28 days prior to the study and continued at the same dose throughout the study. Voclosporin was orally administered at a dose of 23.7 mg twice a day for 7 consecutive days (Days 1–7), starting on the evening of Day 1 and ending with the morning dose on Day 7. Dense pharmacokinetic blood samples were collected pre-dose in the morning and from 0.25 to 12 h after the morning doses. Analyses were derived by non-compartmental methods. Results In 24 patients, MPA exposure [maximum serum concentration (C max) and area under the concentration curve from time 0 to 12 h (AUC0–12)] was similar in the presence and absence of voclosporin, with treatment ratios of 0.94 and 1.09, respectively [ C max 16.5 μg/mL (Day 1) versus 15.8 (Day 7), AUC0–12 39.1 μg/h/mL (Day 1) versus 40.8 (Day 7)]. MPAG exposure showed a small increase in the presence of voclosporin (12% for C max and 27% for AUC0–12). Combination therapy was well tolerated. Conclusions There is no clinically meaningful interaction between voclosporin and MMF. As changes in exposure to MPA may affect efficacy and safety, these data confirm that voclosporin and MMF can be administered concomitantly without the need for dose adjustment. [ABSTRACT FROM AUTHOR]

Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus. Standard-of-care immunosuppressive therapies achieve poor complete renal response (CRR) rates, with considerable toxicity. This article reviews voclosporin, a novel oral calcineurin inhibitor (CNI) approved for treatment in adults with active LN by the US Food and Drug Administration (the FDA) in January 2021. This review summarizes the chemical properties, pharmacokinetics, and pharmacodynamics of voclosporin, and its efficacy and safety in LN, based on literature review covering PubMed searches, manufacturers' websites, and documents produced by the FDA. Voclosporin is a CNI with a consistent pharmacokinetic–pharmacodynamic relationship resulting from enhanced calcineurin binding and reduced drug and metabolite load. This profile permits therapeutic efficacy in LN at a dose associated with relatively low calcineurin inhibition, and therefore a potentially improved safety profile. Pivotal trials demonstrated a significant benefit of adding voclosporin to standard therapy, with rapid reduction in proteinuria, and a clinically meaningful and significantly higher CRR rate at 1 year. At approved doses for LN, potential advantages of voclosporin versus historical experience with CNIs include lack of need for therapeutic drug monitoring, benign metabolic, lipid and electrolyte profile, and no impact on mycophenolate mofetil levels. [ABSTRACT FROM AUTHOR]

Lupus nephritis (LN) is a serious kidney complication associated with systemic lupus erythematosus (SLE), marked by the immune system's misdirected attack on kidney tissues, resulting in inflammation and compromised filtration. This condition has the potential to progress to end-stage renal disease in about 20% of patients within a decade of diagnosis. Lupus nephritis is more prevalent in females, highlighting the urgent need for effective treatment strategies. This systematic review consolidates findings from 16 research articles that explore various therapeutic options for LN. Key themes include the intricate pathogenesis involving immune complex deposition and the advancing treatment landscape, which encompasses both traditional immunosuppressants such as mycophenolate mofetil (MMF) and cyclophosphamide and newer biologics like belimumab and voclosporin. The review examines the efficacy and safety profiles of these treatments, underscoring the importance of personalized treatment plans based on disease severity and patient-specific factors. While newer therapies show promise for improving renal outcomes, the potential for adverse effects remains a significant concern. A thorough review was conducted to evaluate current research on lupus nephritis, focusing on treatment advancements. Two independent reviewers searched PubMed using targeted terms and MeSH categories, emphasizing studies published since 1990 identified 7898 articles from that, 16 articles met the criteria for inclusion in the study. The evaluation of bias risk was performed according to established protocols. This systematic approach provided a comprehensive analysis of recent developments in lupus nephritis therapy., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Patel et al.)

Copyright of Die Nephrologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Kidney survival rates in lupus nephritis (LN) remain suboptimal, with 10–20% of patients progressing to end-stage kidney disease by 10–20 years. Recently, the landscape of LN management has changed with the advent of new molecules that have demonstrated safety and efficacy in clinical trials. In this review, we approach the current state of LN management, the unmet therapeutic needs, and deep dive into voclosporin, a novel calcineurin inhibitor (CNI) that has demonstrated improved efficacy when added to a mycophenolate mofetil (MMF) and glucocorticoid regimen, without an increase in adverse events. We focus on the characteristics of this new CNI and the studies that led to its approval by the US FDA. Voclosporin adds to therapeutic options for LN. This drug offers potential advantages over other CNIs. The addition of voclosporin to a standard-of-care regimen of MMF/glucocorticoids demonstrated higher and faster response rates. As other regimens, a combination of CNI, MMF, and glucocorticoids must be individualized and is not appropriate for all patients. Some questions remain to be answered for this regimen, such as the length of treatment, the tapering schedule, and its long-term safety and efficacy for preserving kidney function. [ABSTRACT FROM AUTHOR]

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) and is one of the leading causes of morbidity and mortality in patients with SLE. It is estimated that up to 60% of individuals with SLE will develop LN, which can manifest at any stage of a patient's life; however, it commonly emerges early in the course of SLE and tends to exhibit a more aggressive phenotype in men compared to women. Black and Hispanic patients are more likely to progress to kidney failure than white patients. LN is characterized by kidney inflammation and chronic parenchymal damage, leading to impaired kidney function and potential progression to kidney failure. This article provides a comprehensive overview of the epidemiology, pathogenesis, clinical presentation, diagnosis, and management of LN, highlighting the importance of early recognition and treatment of LN to prevent progressive, irreversible kidney damage and improve patient outcomes. Additionally, the article discusses current and emerging therapies for LN, including traditional immunosuppressive agents, biological agents, and novel therapies targeting specific pathways involved in LN pathogenesis, to provide a practical guide for clinicians in properly diagnosing LN and determining a patient-centered treatment plan., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to evaluate the potential of voclosporin (VOS) in preventing goblet cell (GC) loss and modulating interferon-gamma (IFN-γ) producing CD4+ T cells in the mouse desiccating stress (DS) dry eye model. Methods: Mice were subjected to DS and treated topically with vehicle, VOS, or cyclosporine A as a treatment control. Corneal barrier function was evaluated after 5 and conjunctival GC density after 10 days of desiccation. CD4+ T cells were isolated from ocular surface draining lymph nodes of dry eye donor mice and adoptively transferred into immune deficient RAG1-/- mice from which tears and conjunctiva were collected for the evaluation of inflammatory cytokines/chemokines and GC density. Results: Compared to the vehicle-treated group, VOS was significantly better in preserving corneal barrier function and preventing DS-induced conjunctival GC loss. CD4+ T cells from VOS treated dry eye donors caused less conjunctival GC loss than vehicle and suppressed expression of IFN-γ signature genes to a similar extent and transforming growth factor-beta to a greater extent than cyclosporine in adoptive transfer recipients. Conclusion: These findings suggest that VOS preserves corneal barrier function and conjunctival GCs and suppresses IFN-γ producing CD4+ T cells in experimental dry eye. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a systemic autoimmune inflammatory disease of unknown cause, with heterogeneity in its clinical presentation, as well as variability in its clinical course and prognosis. The current goal of treatment is to achieve disease remission or a state of low activity, and thereby improve the patient's quality of life. Biological therapy in lupus, unlike other entities, although it has not been fully established, in recent years it has burst onto the scene with important therapeutic novelties. This review aims to update the therapeutic tools for the treatment of SLE focusing on the new molecules that have achieved the objectives of their clinical trials., (Copyright © 2023 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.)

Lupus nephritis (LN) is a serious manifestation of systemic lupus erythematosus that can lead to end-stage renal disease. Many clinical and prognostic data on which our therapeutic decisions are based come from international cohorts, which have important ethnic and prognostic differences. To identify clinical and prognostic data from patients with LN in Spain, we undertook a bibliographic search of NL-related papers by Spanish authors and published in national and international journals between 2005 and 2022. According to the selected references, renal biopsy is not only essential for LN diagnosis but its repetition can be useful for the follow-up. Regarding LN treatment, standard strategy consists of an induction phase and a maintenance phase. However, as new drugs have been released, a new paradigm of treatment in a single, continuing and personalized phase has been proposed., (Copyright © 2023 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Voclosporin is a highly potent, new cyclosporine-A derivative that is currently in Phase 3 clinical trials in the USA as a potential treatment for inflammatory diseases of the eye. Voclosporin represents a number of very sparingly soluble drugs that are difficult to administer. We therefore selected it as a model drug that is dispersed within amphiphilic polymer matrices, and investigated the changing morphology of the matrices using neutron and x-ray scattering during voclosporin release and polymer resorption. The hydrophobic segments of the amphiphilic polymer chain are comprised of desaminotyrosyl-tyrosine ethyl ester (DTE) and desaminotyrosyl-tyrosine (DT), and the hydrophilic component is poly(ethylene glycol) (PEG). Water uptake in these matrices resulted in the phase separation of hydrophobic and hydrophilic domains that are a few hundred Angstroms apart. These water-driven morphological changes influenced the release profile of voclosporin and facilitated a burst-free release from the polymer. No such morphological reorganization was observed in poly(lactide-co-glycolide) (PLGA), which exhibits an extended lag period, followed by a burst-like release of voclosporin when the polymer was degraded. An understanding of the effect of polymer composition on the hydration behavior is central to understanding and controlling the phase behavior and resorption characteristics of the matrix for achieving long-term controlled release of hydrophobic drugs such as voclosporin.

Background and Aims: Acute severe steroid-refractory ulcerative colitis remains a medically challenging condition with frequent need of surgery. It can be treated with the calcineurin inhibitor cyclosporine A with the need for therapeutic drug monitoring and significant toxicity. Recently, a novel calcineurin inhibitor, voclosporin, has been approved for the treatment of lupus nephritis with no need for therapeutic drug monitoring and an improved long-term safety profile. However, the therapeutic effect of voclosporin in acute severe steroid-refractory ulcerative colitis is still uncertain. We aimed to assess the therapeutic potential of voclosporin to ameliorate inflammation in an experimental model of colitis., Methods: We used the dextran sodium sulfate-induced model of colitis in C57BL/6 J wildtype mice treated with either cyclosporine A, voclosporin or solvent control. We employed endoscopy, histochemistry, immunofluorescence, bead-based multiplex immunoassays and flow cytometry to study the therapeutic effect of calcineurin inhibitors in a preventive setting., Results: Acute colitis was induced by dextran sodium sulfate characterized by weight loss, diarrhea, mucosal erosions and rectal bleeding. Both cyclosporine A and voclosporin strongly ameliorated the course of disease and reduced colitis severity in a similar manner., Conclusion: Voclosporin was identified as biologically effective in a preclinical model of colitis and may be a potential therapeutic option in treating acute severe steroid-refractory ulcerative colitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lindemann, Roth, Koop, Neufert, Zundler, Atreya, Neurath and Leppkes.)