Formulation Of Cyclosporine Research Articles

Quintessence of currently approved and upcoming treatments for dry eye disease.

Dry eye disease (DED), also known as dry eye syndrome, is a multifactorial ocular surface disease. The aim of this review is to present the details of currently approved and upcoming treatment options for DED in a nutshell. We conducted a thorough literature search using PubMed and searched US FDA website, clinicaltrials.gov, and data available in public domain for currently approved and upcoming treatment options for DED. Currently, the US Food and Drug Administration (FDA)-approved medical treatments for treatment of DED include cyclosporine formulations (RESTASIS® [cyclosporine 0.05% ophthalmic emulsion], VEVYE® [cyclosporine 0.1% ophthalmic solution], and CEQUA™ [cyclosporine 0.09% ophthalmic solution]), XIIDRA® (lifitegrast), a leukocyte function-associated antigen-1 (LFA-1)/intracellular adhesion molecule-1(ICAM-1) inhibitor, EYSUVIS™ (loteprednol etabonate ophthalmic suspension 0.25%), a corticosteroid, and MIEBO™ (perfluorohexyloctane ophthalmic solution), a semifluorinated alkane. TYRVAYA™ (varenicline solution nasal spray), a cholinergic agonist, is another formulation approved for the treatment of the signs and symptoms of DED. The medical devices approved for treating DED due to meibomian glands dysfunction (MGD) include Lumenis OptiLight™ (intense pulsed light [IPL] device), TearCare® system, and TearScience™ LipiFlow™ thermal pulsation system. Punctal plugs are another treatment option approved for management of DED. There are hundreds of clinical studies evaluating newer treatments for managing the signs and symptoms. Cyclosporine formulations TJO-087 (cyclosporine A nanoemulsion 0.08%), SCAI-001 eye drops (cyclosporine 0.01%, 0.02%) are being evaluated against RESTASIS® and other approved treatments. The potential treatments being assessed include IC 265, OK-101, PL9643, SYL1001 (tivanisiran), SHJ002, OXERVATE® (cenegermin-bkbj ophthalmic solution 0.002%), HBM9036 (tanfanercept ophthalmic solution), OCS-02 (licaminlimab), MIM-D3 (tavilermide ophthalmic solution 5%), AR-15,512, BRM421, reproxalap, and AZR-MD-001 (selenium sulphide ointment 0.5%). The pathophysiology of DED is complex and multifactorial; there is a need to understand it even deeper. The new treatments and different delivery systems seem promising and provide a hope of effective treatment for DED.

Comparative efficacy of cyclosporine 0.1%, rebamipide 2%, and carboxymethylcellulose-cyclosporine 0.05% combination eye drops in the management of dry eye disease among the Indian population

This comparative research study aims to evaluate and compare the results of three different eye drop formulations of Cyclosporine 0.1%, Rebamipide 2%, and a combination of Carboxymethylcellulose & Cyclosporine 0.05%, in treating dry eye cases among the Indian population. This investigation employed a randomized controlled trial design to assess the efficacy of three distinct eye drop formulations. A total of 120 patients diagnosed with dry eye disease participated in this study. Participants were assigned to one of three treatment groups: Group C (cyclosporine 0.1%), Group R (rebamipide 2%), or Group CC (combination of carboxymethylcellulose and cyclosporine 0.05%). Patients take prescribed medication for six weeks. Patients were evaluated at baseline for tear production time (TFBUT) at two weeks, four weeks, and six weeks, tear production score using the Schirmer test, and dry eye symptoms were assessed with the Ocular Surface Disease Index (OSDI). The collected data were analyzed using appropriate tests to compare the effectiveness of three eye drop formulations in treating dry eye in the Indian population. : Disease improvement compared to baseline was seen in all groups based on scoring of Schirmer's score, OSDI score, and TBUT. : All three treatment groups demonstrated improvements in tear film stability, tear production, and a reduction in dry eye symptoms over the six-week treatment period. However, further research with larger sample sizes and longer treatment durations is needed to establish the long-term efficacy and compare the effectiveness of these treatments.

Cyclosporine ophthalmic emulsion (Verkazia) for vernal keratoconjunctivitis.

The FDA has approved Verkazia (Santen), a 0.1% ophthalmic emulsion formulation of the calcineurin inhibitor cyclosporine, for treatment of vernal keratoconjunctivitis (VKC). Verkazia is the first product to be approved in the US for this indication.

Efficacy and safety of 0.05% micellar nano-particulate (MNP) cyclosporine ophthalmic emulsion in the treatment of moderate-to-severe keratoconjunctivitis sicca: a 12-week, multicenter, randomized, active-controlled trial

BackgroundKeratoconjunctivitis sicca or dry eye disease (DED) is a multifactorial disorder underpinned by a complex inflammatory cycle. Introduction of topical cyclosporine has been a significant advance in the management of DED. In recent years advancements in formulation technology have led to development of micellar nano-particulate (MNP) cyclosporine formulations that promise better penetration into ocular target tissues and potential for reduced ocular surface irritation.MethodsWe compared two dosing regimes of a proprietary MNP cyclosporine emulsion with the widely marketed topical cyclosporine formulation Restasis™ in a multicenter parallel-group randomised trial in patients with DED. Patients were randomised to one of 3 treatment groups with 90 patients eligible for the per protocol analysis: 30 in the higher dose test arm A; 32 in the lower dose test arm B; and 28 in the Restasis™ control arm C. All scored efficacy endpoints were tested for significance by comparing the mean change in scores from baseline in the test groups with that in the control group at 12 weeks, using the Student’s t test. Wilcoxon’s rank sum test was used to test individual symptom scores and clinician’s global evaluation of treatment grades.ResultsCorneal fluorescein staining score, the primary efficacy endpoint, decreased by 6.8 ± 4.0, 5.7 ± 3.9, and 4.6 ± 3.6 points in the 3 groups respectively, indicating superior efficacy in test arm A in comparison to control arm C (p = 0.0026). Schirmer’s tear test, conjunctival lissamine staining score, ocular surface disease index, and individual dry eye symptom scores also favoured higher dose MNP cyclosporine over Restasis™. The study failed to differentiate the treatment arms in terms of clinician’s global evaluation of treatment, use of tear substitutes, best corrected visual acuity or safety and toleration.ConclusionThe results indicate that the dose of 1 drop of a 0.05% w/v ophthalmic emulsion of MNP cyclosporine administered topically twice daily yields better outcomes at 12 weeks than the lower dose tested in the study, and is more efficacious than an equivalent dose of Restasis™, the active control used in the study.Trial registrationThis trial was registered in the Clinical Trials Registry of India on 29/03/2019, and was assigned registration number CTRI/2019/03/018319.

A novel formulation of cyclosporine A/phosphatidylserine-containing liposome using remote loading method: Potential product for immunosuppressive effects

In this study, two PEGylated and non-PEGylated liposomal formulations of Cyclosporine A (CsA) were prepared by remote loading procedure to improve the tissue distribution profile of CsA and the therapeutic efficacy thereof. DOPE/DOPS/Chol/α-Tocopherol/mPEG2000 (35/40/19.5/0.5/5) and DOPE/DOPS/Chol/α-Tocopherol (40/40/19.5/0.5) were examined in terms of their physicochemical stability, immunosuppressive efficiency, and pharmacokinetic profiles. Besides, the delayed-type hypersensitivity reaction (DTH) was studied from sheep red blood cells (SRBC) injection to male Wistar rats and skin allograft rejection transplanted from male C57BL into BALB/c mouse. Both liposomes had a size of about 162.2 ± 75 nm with a polydispersity index of <0.14, exhibited a high drug encapsulation efficacy (49.9–61.3%), and showed a long-term (6 months) shelf-life stability. Moreover, the liposomes enhanced the delivery of CsA and the improved immunosuppressive efficiency in vitro compared to non-liposomal CsA. In the animal studies, the liposomes also enhanced the drug half-life in the serum of the rat and improved the tissue distribution of CsA compared to non-liposomal CsA. Besides, the liposomes minimized the DTH and delayed the skin allograft rejection up to 17 days compared to CsA. To sum up, the liposomal formulations of CsA improved both the delivery profile and therapeutic efficacy of CsA. However, further studies need to be done to translate this formulation into the clinics.

The Potential Use of Cyclosporine Ultrafine Solution Pressurised Metered- Dose Inhaler in the Treatment of COVID-19 Patients.

Serious COVID-19 respiratory problems start when the virus reaches the alveolar level, where type II cells get infected and die. Therefore, virus inhibition at the alveolar level would help preventing these respiratory complications. A literature search was conducted to collect physicochemical properties of small molecule compounds that could be used for the COVID-19 treatment. Compounds with low melting points were selected along with those soluble in ethanol, hydrogen-bond donors, and acceptors. There are severe acute respiratory syndrome coronavirus inhibitors with physicochemical properties suitable for the formulation as an ultrafine pressurised metered-dose inhaler (pMDI). Mycophenolic acid, Debio 025, and cyclosporine A are prime candidates among these compounds. Cyclosporine A (hereafter cyclosporine) is a potent SARS-CoV-2 inhibitor, and it has been used for the treatment of COVID-19 patients, demonstrating an improved survival rate. Also, inhalation therapy of nebulised cyclosporine was tolerated, which was used for patients with lung transplants. Finally, cyclosporine has been formulated as a solution ultrafine pMDI. Although vaccine therapy has started in most countries, inhalation therapies with non-immunological activities could minimise the spread of the disease and be used in vaccine-hesitant individuals. Ultrafine pMDI formulation of cyclosporine or Debio 025 should be investigated for the inhalation therapy of COVID-19.

The Effect of OTX-101 on Tear Production in Patients with Severe Tear-deficient Dry Eye Disease: A Pooled Analysis of Phase 2b/3 and Phase 3 Studies

ABSTRACT Purpose Impaired tear production – a common sign of keratoconjunctivitis sicca (KCS) – is associated with qualitative or quantitative tear deficiency. OTX-101 0.09% is a novel, nanomicellar formulation of cyclosporine A approved in the US for increasing tear production in patients with KCS. We present a pooled analysis of the phase 2b/3 and phase 3 studies evaluating the effect of OTX-101 on tear production in a subgroup of patients with keratoconjunctivitis sicca with severely impaired tear production (Schirmer’s score <5 mm in either eye at baseline). Methods In these randomized, double-masked studies, patients instilled 1 drop OTX-101 or vehicle per eye twice daily for 84 days. Pooled efficacy endpoints included percent (%) of patients with ≥10 mm change from baseline and mean change from baseline in Schirmer’s score at day 84. Pooled safety endpoints included adverse event monitoring. Results Subgroup analyses included 133 and 113 patients receiving OTX-101 and vehicle, respectively. Mean baseline (BL) Schirmer’s score ± standard deviation was 2.7 ± 1.2 for OTX-101 and 2.5 ± 1.1 mm for vehicle (P = .3203). On day 84, number (%) of patients with ≥10 mm Schirmer’s score change from baseline was 30 (22.6%) and 12 (10.6%, P = .0168); mean change from baseline ± standard deviation was 5.5 ± 8.0 and 3.6 (6.0, P = .0405) mm for OTX-101 and vehicle, respectively. Adverse events were mostly mild and did not require treatment. Conclusion OTX-101 administered twice daily for 84 days significantly improved tear production vs vehicle in patients with severely impaired tear production, as evidenced by significantly larger proportion of patients with ≥10 mm increases from baseline and higher mean change from baseline in Schirmer’s scores

Cyclosporine Lipid Nanocapsules as Thermoresponsive Gel for Dry Eye Management: Promising Corneal Mucoadhesion, Biodistribution and Preclinical Efficacy in Rabbits.

An ophthalmic cyclosporine (CsA) formulation based on Lipid nanocapsules (LNC) was developed for dry eye management, aiming to provide targeting to ocular tissues with long-term drug levels and maximum tolerability. CsA-LNC were of small particle size (41.9 ± 4.0 nm), narrow size distribution (PdI ≤ 0.1), and high entrapment efficiency (above 98%). Chitosan (C) was added to impart positive charge. CsA-LNC were prepared as in-situ gels using poloxamer 407 (P). Ex vivo mucoadhesive strength was evaluated using bovine cornea, while in vivo corneal biodistribution (using fluorescent DiI), efficacy in dry eye using Schirmer tear test (STT), and ocular irritation using Draize test were studied in rabbits compared to marketed ophthalmic CsA nanoemulsion (CsA-NE) and CsA in castor oil. LNC incorporation in in-situ gels resulted in an increase in mucoadhesion, and stronger fluorescence in corneal layers seen by confocal microscopy, compared to the other tested formulations. Rate of recovery (days required to restore corneal baseline hydration level) assessed over 10 days, showed that CsA-LNC formulations produced complete recovery by day 7 comparable to CsA-NE. No Ocular irritation was observed by visual and histopathological examination. Based on data generated, CsA-LNC-CP in-situ gel proved to be a promising effective nonirritant CsA ophthalmic formulation for dry eye management.

Efficacy, Safety, and Tolerability of a Novel Cyclosporine, a Formulation for Dry Eye Disease: A Multicenter Phase II Clinical Study

PurposeThe purpose of this study was to explore the efficacy, safety, and tolerability of a novel cyclosporine formulation for dry eye disease (DED). MethodsThis is an exploratory, multicenter, single-blind, randomized, positive-controlled Phase II clinical trial between cyclosporine ophthalmic gel (CyclAGel) and an open-label comparator (Restasis, positive control). A total of 240 eligible patients with moderate to severe DED were randomized to 4 study groups: CyclAGel 0.05%/once daily (QD) (n = 59), CyclAGel 0.05%/BID (n = 60), CyclAGel 0.1%/QD (n = 60), and Restasis 0.05%/BID (n = 61). After receiving BID dosing of hypromellose eye drops during a 2-week run-in period, patients were randomized to the respective treatment group and dosed QD or BID for 12 weeks. Efficacy was assessed based on a number of sign and symptom end points, including eye dryness score (visual analog scale), 6 other parameters of symptoms for dryness (burning/stinging, itching, foreign body sensation, discomfort, sensitivity to light, and pain), and corneal fluorescein staining. The Schirmer test was used to assess dry eye symptoms (visual analog scale severity) at visit 3 (week 2), visit 4 (week 6), and visit 5 (week 12). FindingsCyclAGel showed a consistent improvement in eye dryness score and the 6 other parameters of symptoms for dryness, corneal fluorescein staining, breakup time, and Schirmer test scores compared with Restasis over the 12-week treatment period. However, there were no statistically significant differences between CyclAGel and Restasis after baseline corrections were made, and the results of the full analysis set remained consistent with those of the per-protocol set (P > 0.05). Moreover, each CyclAGel-treated group (0.05%/QD, 0.05%/BID, and 0.1%/QD) exerted better effects than the Restasis group, and CyclAGel 0.05%/QD showed the most significant improvement. The number of ocular-related treatment-emergent adverse events was low in all treatment groups, with no serious drug-related treatment-emergent adverse events. ImplicationsCyclAGel showed excellent safety, tolerability, and comfort profiles at 2 concentrations and frequency in moderate to severe DED.

A Review of the Mechanism of Action of Cyclosporine A: The Role of Cyclosporine A in Dry Eye Disease and Recent Formulation Developments.

Dry eye disease (DED) is a multifactorial disease of the ocular surface and tear film that has gained awareness as a public health problem. Characteristics of DED include tear film instability, hyperosmolarity, and ocular surface inflammation, which can occur independently or may be a sequela of numerous ocular diseases, ocular surgery or contact lens wear. Much has been learned about the impact of the disease to help affected individuals who report symptoms of poor vision, pain, and tearing. Recently, new research highlights the importance of the role of ocular surface inflammation and damage in DED—leading to a vicious cycle of inflammation as well as loss of tear film homeostasis. DED immunopathophysiology is characterized by four stages: initiation, amplification, recruitment, and re-initiation. Cyclosporine is proven to be a valuable ophthalmic therapeutic for DED through its immunomodulatory actions and regulation of the adaptive immune response. Cyclosporine mechanism of action is well described in the published literature and the myriad of benefits in all four stages lend a broad-based immunomodulatory function particularly suitable for addressing DED. Furthermore, cyclosporine has unique goblet cell density improvement capabilities as well as anti-apoptotic properties. Topical formulations of cyclosporine are centered around addressing the highly lipophilic nature of the molecule. The poor aqueous solubility of cyclosporine traditionally presented technical challenges in drug delivery to the ocular surface. Newer formulations such as cationic emulsions and nanomicellar aqueous solutions address formulation, tissue concentration, and drug delivery challenges.

Cyclosporine CsA—The Physicochemical Characterization of Liposomal and Colloidal Systems

This paper presents an overview of the possibilities of testing various cyclosporine (CsA) formulations with an emphasis on parameters that may be key to improving the stability and biocompatibility. The feasibility of CsA colloidal systems for oral (injection) administration were investigated using different techniques and compared with similar investigations of other researchers. The chosen CsA systems were developed using dipalmitoylphosphocholine (DPPC) and/or cholesterol as a lipid matrix, stabilized with ethanol, with soybean oil or n-tetradecane as oil phase in emulsions, under natural pH, room and physiological temperature. Their integrity was found to be strictly dependent on the stabilizers. The highest CsA penetrability with the system containing phospholipid in the context of its interactions with lipid membranes was shown. Also, the bioavailability of CsA can be enhanced with the biopolymer antibacterial chitosan. This mini-review suggests the suitability of liposome/microemulsion as promising vehicles for CsA delivery. The most hopeful proved to be formulation with the smaller particle size facilitating absorption, but when safety is assessed, relying on just the particle size cannot be the only criteria. Reassumed, the CsA formulation stability known on the basis of the size and zeta potential measurements guarantees a decrease of the individual variations in the drug bioavailability, toxicity and minimizes rejection.

Topical nano-encapsulated cyclosporine formulation for atopic dermatitis treatment

Systemic cyclosporine A (CsA) therapy shows efficacy in the treatment of recalcitrant severe atopic dermatitis (AD) but elicits severe side-effects. Thus, a topical formulation of CsA nanocapsules (NCs), able to potentially bypass these drawbacks, was developed. CsA-NCs were shown to enhance drug penetration into the various layers of porcine ear skin. Furthermore, the encapsulated CsA was biologically active, as shown in vitro on mouse splenocytes, reflected by inhibition of both cell proliferation and of interleukin (IL)-2 secretion. Ex-vivo efficacy was demonstrated on human skin organ culture by markedly reducing pro-inflammatory cytokines secretion. Finally, CsA-NCs topical formulation elicited improved efficacy in terms of better preservation of the skin barrier integrity, a decrease of the systemic pro-inflammation markers and reduced skin inflammation. The overall results suggest that this original topical platform may provide a novel therapeutic tool of clinical significance compared to the existing topical therapeutic drugs in AD.

Effect of Cyclosporine Inhalation Solution (CIS) on Lung Function and Inflammatory Biomarkers in Patients with Hematopoietic Stem Cell Transplant (HSCT) Associated Bronchiolitis Obliterans Syndrome (BOS)

Background: Chronic graft versus host disease of the lungs may result in bronchiolitis obliterans syndrome (BOS), an inflammatory injury to medium size airways leading to fibrosis. BOS is often treated with an increase in immunosuppression which can be associated with systemic complications (e.g. organ dysfunction, increased susceptibility to infection and blunting of graft versus leukemia effect). In order to provide enhanced local delivery of an immunosuppressant, cyclosporine, we studied the effects of cyclosporine inhalation solution (CIS) in allogeneic hematopoietic stem cell transplant (HSCT) patients with BOS with a short-term assessment of lung function and inflammatory markers in blood and bronchoalveolar lavage (BAL). Methods: Patients who underwent an allogeneic HSCT meeting the NIH consensus clinical definition of BOS were eligible for inclusion, and were treated with CIS and monitored for treatment response with serial pulmonary function tests (PFTs). At baseline, patients were classified as having stable or progressive disease (i.e. &gt; 10% decline in forced expiratory volume in one second (FEV1) in the preceding 18 weeks). Response was defined as either improvement or stabilization at week 18. Improvement was defined as an increase in FEV1 (regardless of baseline categorization) &gt; 10%. Stabilization was defined as FEV1 increase or decrease &lt; 10% in patients with progressive disease at baseline, and with a reduction in systemic immunosuppression by 25% in those with stable disease at baseline. Patients with declining FEV1 &gt; 10% were classified as non-responders, and patients with FEV1 decline &gt; 20% or with worsening clinical status were taken off protocol. BALs were performed at study entry and week 18 of treatment. BAL and serum samples were analyzed via a custom Luminex® panel. The 37 analytes studied included the following categories: 1) chemokines (CCL2, 3, 5, 18; CXCL5, 9, 10, 13), 2) cytokines (IL-1β, -1ra, -2, -2rα, -6, -7, -8, -10, -12p70, -15, -17a, -23, -17E/25, TNFα, IFNγ), 3) matrix metalloproteinases (MMP1-3, 7-9, 12-13), 4) growth-factors (VEGF-α, G-CSF), and 5) others (PD-L1, surfactant protein D, osteopontin, myeloperoxidase). Results: In total, 20 HSCT patients with BOS were enrolled (median age 45.5 yrs: range 14-71; 13 men and 7 women), and 11 patients completed the study through week 18. The average time from transplant was 4.6 yrs (range 1-28, median 3 yrs). Baseline FEV1 was 1.18 liters (range 0.5-2.02), and with an average FEV1 of 36% predicted (range 18-56%). At the time of enrollment, 12 patients had stable disease, and 8 had progressive disease. Nine patients discontinued treatment due to either worsening FEV1 by 25% (n=1), relapse of primary disease (n=1), or side effects (n=7; cough and bronchospasm). Sixteen patients were included in the evaluable patient population (patients who received treatment for at least the first two weeks) with 9 responders (4 with improvement, 5 with stabilization) and 7 non-responders. Among those completing the study (n=11), 4 had improvement in FEV1, 5 had stable disease, and 2 were non-responders. Seven patients were continued on CIS through an extended use protocol. The baseline BAL cell differentials demonstrated a neutrophil predominance (66 + 29 %) that persisted at week 18 (56 + 35%). In the BAL, MMP-7 increased from baseline (150 + 215 pg/mL) to week 18 (1956 + 2624 pg/mL; p value 0.049), while soluble PD-L1 levels fell (97 + 55 pg/mL to 55 + 43 pg/mL; p value 0.04). The other categories of biomarkers in BAL were either undetectable (n = 12) or demonstrated no significant difference (n = 23) in patients with or without a clinical response to CIS. Similarly, concomitant serum biomarkers showed no difference in treatment after CIS, even when classified amongst responders and non-responders. Conclusion: In HSCT-BOS, CIS led to an improvement or stabilization of PFTs and/or a decrease in systemic immunosuppression in 9 of the 11 patients that completed the study. Due to cough and bronchospasm, only 11 of 20 patients were able to complete treatment through week 18. Inflammatory markers in the serum and BAL were not elevated at baseline or at the end of study. These data suggest that later stages of BOS may represent progression from a state of inflammatory injury to a fibrotic process. Based on our findings, we believe patients with later stage BOS may benefit from investigational therapeutics targeting lung remodeling. Figure Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Not really. This drug is not commercially available or FDA approved. An IND was obtained for the use of an inhaled formulation of cyclosporine. Aerosolized cyclosporine has been used previously in other patients (lung transplant associated BOS)

Effect of OTX-101, a Novel Nanomicellar Formulation of Cyclosporine A, on Corneal Staining in Patients With Keratoconjunctivitis Sicca: A Pooled Analysis of Phase 2b/3 and Phase 3 Studies: Erratum.

Effect of OTX-101, a Novel Nanomicellar Formulation of Cyclosporine A, on Corneal Staining in Patients With Keratoconjunctivitis Sicca: A Pooled Analysis of Phase 2b/3 and Phase 3 Studies: Erratum.

713 A Randomized, Multicenter, Double-Blind, Placebo-Controlled Study of a Targeted Release Oral Cyclosporine Formulation in the Treatment of Mild to Moderate Ulcerative Colitis: Influence of Immunosuppressants at Baseline

INTRODUCTION: Patients (pts) with ulcerative colitis (UC) who have failed immunosuppressants (IM) and biologics have demonstrated poorer response to subsequent therapies. 1 Cyclosporine (CsA) could be an alternative option since it has similar efficacy and safety to infliximab for severe UC, 2 but its use is limited due to concerns regarding systemic toxicity. ST-0529 is a novel oral formulation of CsA that delivers the drug directly to the colon, allowing for precise targeting of the diseased tissue while potentially limiting the risk of systemic toxicity. METHODS: A phase IIa study was conducted in a total of 118 subjects with baseline Disease Activity Index (DAI) &lt; 6 (mild UC) or ≥6 (moderate UC), randomized 1:1 to receive 75 mg ST-0529 once daily (n = 53) or placebo (n = 65) for 4 weeks. The primary endpoint was the induction of clinical remission (DAI score ≤2, with no individual score &gt;1 and rectal bleeding subscore of 0 or 1). The secondary endpoints were safety and tolerability, mucosal healing, clinical response, and histological healing. 3,4 Post-hoc subgroup analysis was conducted in 93 subjects with moderate UC, of whom 75 received at baseline 5-ASA alone or in combination (n = 51, with/without steroids; n = 24, with/without IM) to evaluate the impact of them on clinical improvement (DAI reduction ≥3) and composite subscores (rectal bleeding and stool frequency with or without mucosal appearance evaluation). RESULTS: Table 1 shows the influence of baseline medications on the improvement of DAI scores in subjects with moderate UC, and Tables 2 and 3, the impact of IM on the analyzed parameters. Safety was balanced for the overall population. CONCLUSION: This analysis showed that clinical improvement and composite subscores were influenced by baseline medication in pts with moderate UC. The poorer response in the IM treated group was potentially a function of severity or refractory disease and/or concomitant use of UC medication (prednisone &lt; 10 mg/day, 5-ASAs or purine analogues) at baseline. Concomitant UC medications were not restricted at study entry as long as pts maintained stable dosing regimens throughout. These preliminary data support further investigation of ST-0529 usage as a twice daily treatment for the induction and maintenance of remission in UC pts with moderate disease, which will be the focus of the phase IIb trial.

Preventing medication errors involving different formulations of cyclosporine

Patients who receive solid organ or allogeneic hematopoietic stem cell transplants are required to take long-term immunosuppressant drugs to prevent rejection and graft-versus-host disease. The drug and dosage selection of immunosuppressants is usually individualized for the patient based on the type of transplant, target blood level, body weight, drug–drug interactions, and the risk of rejection or toxicity. The complexity of the selection process can introduce the risk for errors. Almost 20 years ago, ISMP alerted health care practitioners about Sandimmune (cyclosporine capsules and oral solution) and how this nonmodified form of the drug has decreased bioavailability compared with Neoral or Gengraf (cyclosporine [modified] capsules and oral solution). At the time, a survey by Novartis identified that 24% of prescriptions failed to specify which form of the drug should be dispensed, and only 22% of these prescriptions were clarified. We mention this because, 20 years later, we are still receiving reports of patients receiving Sandimmune when the prescriber’s preference was for a cyclosporine (modified) oral formulation. For example, three patients received Sandimmune instead of the more appropriate form of the drug, Neoral or Gengraf. In another case, during medication reconciliation, a nurse documented that a hospitalized patient was taking cyclosporine but did not verify the brand name to determine the form of the drug. The patient’s physician prescribed Sandimmune, and the patient received a dose before a pharmacy technician discovered that the patient had recently filled a prescription for Gengraf. Many transplant centers use oral solution formulations of immunosuppressant agents to allow greater flexibility in dosage adjustments, especially for pediatric patients. In one case, a 10-fold overdose of cyclosporine (modified) oral solution was administered to a child. The physician prescribed 0.5 mL (50 mg), and the pharmacy dispensed a sealed package of the medication (100 mg/mL), which contained a 5-mL oral syringe provided by the manufacturer that was calibrated in 1-mL increments, with hash marks between each milliliter. The child’s parent administered 5 mL (500 mg) instead of 0.5 mL to the child for several days. Since immunosuppressant agents have significant interpatient dosing variability, dosage delivery devices need to be selected specifically for each patient, and one size does not fit all. In this case, the 5-mL syringe size was significantly larger than each intended dose and did not facilitate accurate measurement and delivery of the prescribed dose. If the pharmacy that dispensed the cyclosporine had used a teach-back method during counseling, for instance, the dosing error might have been avoided. Cyclosporine and cyclosporine (modified) products are not interchangeable. Blood levels must be monitored to prevent serious consequences if a transplant patient receives the wrong formulation. Consider the following recommendations to reduce the risk of errors:▪Prescribers should indicate the brand name, and pharmacists should clarify prescriptions for cyclosporine.▪Order entry systems should clearly display these different forms of the drug, and a hard stop should force verification of the correct drug form during prescribing.▪Upon dispensing an oral solution, pharmacists should evaluate the appropriateness of the dosage delivery device included in the package. To improve accuracy and safety, select the dosage delivery device that will work best for the patient and his or her specific dose. A 2017 study found that providing dosing devices that closely matched the prescribed volume per dose offered the greatest reduction of errors.1.Yin H.S. et al.Pediatrics. 2017; 140 (e20163237)Google Scholar▪Health professionals, using a teach-back method, should ask patients and caregivers to show them how they will withdraw and measure oral liquid medications using their dosage delivery device.

Effect of OTX-101, a Novel Nanomicellar Formulation of Cyclosporine A, on Conjunctival Staining in Patients with Keratoconjunctivitis Sicca: A Pooled Analysis of Phase 2b/3 and 3 Clinical Trials.

Purpose: Keratoconjunctivitis sicca (KCS), a multifactorial disease, is the most common ocular condition for patients seeking medical treatment and is characterized by ocular burning, stinging, and dryness. This pooled analysis examined the effect of OTX-101 0.09% versus vehicle on the total and individual conjunctival staining in patients with KCS from phase 2b/3 and phase 3 studies. Methods: In these randomized, multicenter, double-masked, and vehicle-controlled studies, patients received 1 drop of OTX-101 0.09% or vehicle in both eyes twice daily. The time points for the pooled analysis were baseline (day 0) and study days 28, 56, and 84/early discontinuation. Conjunctival staining was graded on a 0- to 3-point scale per zone and averaged over both eyes at each assessment. Pooled safety assessments included adverse event (AE) reporting. Results: The total mean (standard deviation) conjunctival staining scores at baseline were 5.4 (1.7) for OTX-101 (n = 523) and 5.5 (1.7) for vehicle (n = 525). OTX-101 versus vehicle significantly reduced the total conjunctival staining scores (P = 0.0316, <0.0001, and 0.0002) for days 28, 56, and 84, respectively. The most common treatment-related AE was instillation site pain (21.8% OTX-101 vs. 4.0% vehicle); most AEs were mild in nature. Conclusions: Treatment with OTX-101 versus vehicle significantly improved the conjunctival staining in KCS as early as 4 weeks, and the improvement was maintained through 12 weeks. OTX-101 was effective and well tolerated for use in KCS.

Comments on the dilemma in the June issue: Not a dry eye in the house: treating rescue dogs with off-licence cyclosporine

In the dilemma discussed in the June issue of In Practice, David Williams described a scenario where you are presented with a puppy that has abnormal eye discharge which, on...

Recent advances in cyclosporine drug delivery: challenges and opportunities.

Cyclosporine has been established as a gold standard for its immunosuppressant action. Apart from this, the molecule is boon in treating broad spectrum of diseases like rheumatoid arthritis, psoriasis, and dry eye syndrome. The broad spectrum of cyclosporine demands efficient delivery systems by several routes. Neoral® and Sandimmune® are currently available formulations for oral route, whereas Restasis® is used for ocular delivery of cyclosporine. The available formulations serve the purpose only to a limited extent due to constraints like high molecular weight, low solubility, low permeability, bitter taste, and narrow therapeutic index of cyclosporine. Therefore, several novel formulations like microemulsion, self-emulsifying systems, nanoparticles, and microspheres were developed to overcome these constraints, exploring different routes like oral, ocular, and topical for cyclosporine. Additionally, iontophoresis and ultrasound-mediated delivery has also been studied to improve its poor permeability in topical delivery, whereas biodegradable implants were reported to increase the retention time in cornea and prolonged the release of cyclosporine by ocular route. Although these recent advances in cyclosporine delivery look promising, its clinical translation require in depth studies to deliver safe, efficacious, and stable formulation of cyclosporine. This review focuses on challenges of cyclosporine delivery and the recent advancements for overcoming the constraints.

A Phase 3, Randomized, Double-Masked Study of OTX-101 Ophthalmic Solution 0.09% in the Treatment of Dry Eye Disease

To evaluate the safety and efficacy of OTX-101, a novel aqueous nanomicellar formulation of cyclosporine (0.09%), in the treatment of patients with dry eye disease (DED). A randomized, multicenter, vehicle-controlled, double-masked, phase 3 clinical trial. Adults (18-90 years of age) with a history and clinical diagnosis of DED, a global symptom score of 40 or more (range, 0-100), and a lissamine green conjunctival staining score of 3 or more and 9 or less (range, 0-12) in at least 1 eye. Eligible patients entered a run-in period of 14 to 20 days in which all patients administered vehicle twice daily. Patients who remained eligible at the baseline (day 0) visit were randomized in a 1:1 ratio to twice-daily treatment with OTX-101 0.09% or vehicle for 84 days. Efficacy assessments included signs (unanesthetized Schirmer tear test, corneal and conjunctival staining) and symptoms (global symptom score) of DED. The primary end point was the proportion of eyes with a clinically meaningful improvement (increase of ≥10 mm) in Schirmer test score at day 84. Safety evaluations included adverse events (AEs), visual acuity, and intraocular pressure monitoring, slit-lamp, dilated ophthalmoscopy, and fundus examinations. A total of 744 patients were randomized and received study medication (371 to OTX-101 0.09% and 373 to vehicle). The primary end point was achieved; a significantly greater percentage of eyes in the OTX-101 0.09% treatment group achieved an increase of 10 mm or more in the Schirmer test score at day 84 (OTX-101 0.09%, 16.6%; vehicle, 9.2%; P < 0.001). Significant improvements relative to vehicle also were observed for corneal (days 28, 56, and 84) and conjunctival (days 56 and 84) staining. The global symptom score was reduced from baseline in both treatment groups by approximately 30%; however, no significant separation between groups was observed. The OTX-101 0.09% formulation was well tolerated. Treatment-emergent AEs were primarily mild in intensity. Clinically and statistically significant improvements in tear production and ocular surface integrity were observed in patients treated with OTX-101 0.09% for DED.