Remsima: Uses, Safety, Pharmacodynamics & Pharmacokinetics

Application of Remsima

Critically Appraise The Research & Development Process For New Pharmaceutical Products.

Develop An Integrated Control Strategy To Initiate, Prepare And Conduct a Clinical Study.

Explain The Essential Elements Of a Compliant Drug Safety System.

Outline Regulations & Directives Applicable To Clinical Trials

Describe And Participate In a Simulated Gcp Inspecti7on.

Explain The Format And Structure Of a Clinical Study Reports & Clinical Overview

Remsima is an immunosuppressant whose active substance is infliximab. The infliximab is a monoclonal antibody which is a type of protein that binds to a unique component in the body of the TNF (tumour necrosis factor) alpha (Yooet al. 2017). Remsima falls under a set of medicines which is called ‘TNF blockers’. The Remsima works by specifically binding with the TNF alpha and then blocks its function. TNF alpha is diverged in the inflammatory procedures of the body, thus restricting it can decrease the inflammation inside the body(European Medicines Agency, 2020). Remsima SC is developed at 120 mg/mL and transformed into a solution which is then filled into a syringe. Every syringe is developed to carryone dose of 120 mg infliximab in a 1 mL solution. The Remsima SC drug product is Remsima SC drug product is transformed into a pre-filled syringe (PFS), a pre-filled pen (also referred to as auto-injector AI) assembled with PFS and a pre-filled syringe with an automatic needle guard (PFS-S). Remsima IV is approved for children, adolescents aged between 6 to 17 years and to adult patients(European Medicines Agency, 2020).

The Remsima drug has been authorized to be used upon various inflammatory diseases such as Psoriatic arthritis, Psoriasis, Rheumatoid arthritis, Ankylosing spondylitis (Bechterew’s disease), Ulcerative colitis and Crohn’s disease (Jahnsenand Jørgensen2017).

Rheumatoid arthritis is an inflammatory disease which occurs in the joints. Generally, when a person suffers from rheumatoid arthritis, their healthcare specialist suggests them other medicines and when those medicines do not function properly, then Remsima is suggested as an alternative medicine which is also called methotrexate. Remsima tends to reduce the disease signs and symptoms, slows down joint damage and protects the physical properties (Jahnsen and Jørgensen 2017).

Psoriatic arthritis is another inflammatory disease that occurs in the joints, with which psoriasis also occurs. If a person suffers from psoriatic arthritis,their healthcare specialist suggests them other medicines and when those medicines do not function properly, then Remsima is suggested as an alternative medicine. Remsima helps in decreasing the signs and symptoms of the disease, slows down the pace of the amount of damage to the joints and enhances the physical function(Jahnsen and Jørgensen 2017).

Rheumatoid Arthritis

Ankylosing spondylitis is another inflammatory disease that occurs in the spine. If a person suffers from psoriatic arthritis, their healthcare specialist suggests them other medicines and when those medicines do not function properly, then Remsima is suggested as an alternative medicine. Remsima helps in decreasing the signs and symptoms of the disease, slows down the pace of the amount of damage to the joints and enhances the physical function(Jahnsen and Jørgensen 2017).

Psoriasis is an inflammatory skin disease. If a person suffers from moderate to severe plaque psoriasis, their healthcare specialist will suggest them other medicines such as phototherapy. If those medicines do not function properly, then Remsima is suggested as an alternative medicine as it helps in decreasing clinical manifestation of the disease, slows down the pace of the amount of joint damages and enhances the physical functioning (Jahnsen and Jørgensen 2017).

Ulcerative colitis is an inflammatory bowel disease. If a person suffers from Ulcerative colitis, their healthcare specialist will suggest them other medicines such as phototherapy. If those medicines do not function properly, then Remsima is suggested (Jahnsen2016).

Crohn’s disease is an inflammatory disease of the bowel. An individual suffering from Crohn’s disease, their healthcare specialist will suggest them other medicines. If those medicines do not function properly, then Remsima is suggested in for the treatment of Crohn’sdisease, and the decrease the amount of abnormal openings (fistulae) among the bowel and the skin that could not be managed by particular drugs or surgery.

Since 1999, the intravenous infliximab is being constantly used in Europe for clinical practice and the safety profile of this drug has been consideredafter clinical use for a long 15 years. In the month of September 2013, Europe developed and approved the IV infusion under legislation (EMEA/H/C/002576) as a biosimilar product to EU-approved Remicade. Till 20^th January 2018, there has been 370108 patients on whom the Remsima was used.Even after the well-established clinical safety of intravenous administration of infliximab is well established with longterm safety data, the safety profile of SC administration of infliximab is not known, as the SC formulation of infliximab has not been previously authorized (Gheorghe, Svoboda, Dimitriu, Mateescuand Kotzev2018).

To assess the clinical safety of Remsima, a research was conducted on the use of the infliximab biosimilarRemsima in patients suffering from ulcerative colitis diseaseafter a six months treatment.The research was conducted in the setting of the Hospital UniversitarioVirgen Macarena, Seville, Spain in the month of March 2015 and the research involved 40 patients suffering from ulcerative colitis (UC) (where 31 people switched from Remicade to Remsima and 9 were naïve). After the continuous six months treatment, where 16 patients (15 switch and 1 naïve) were analyzed, 70% patients continued to remain in remission and the other 23% of patients without remission when switched reached remission(Guerra et al., 2016). In around two patients, signs of mild head ache were noted. Through the study, the authors concluded that Remsima is safe for use as most of the patients who were suffering from ulcerative colitis were able to switch from Remicade to Remsimaand  continued to stay in remission after six months of treatment. Though, the researchers conceded that the follow-up was short and that there was no control group, highlighting the need for further studies (Guerra et al., 2016).

Psoriatic Arthritis

Infliximab is a chimeric human murine, monoclonal antibody G1 (IgG1), bound to both soluble and transmembrane forms of TNF-α with high affinity. Remsima IV has been developed and allowed as a biosimilar infliximab. The present request interests Remsima's SC formulation. The same active ingredient as the Remsima IV is found in Remsima SC.

Infliximab disrupts the activation of pro-inflammatory receptor activity. The invasion of inflammatory cells in inflammation areas have been shown to be reduced by infliximab. It also attracts attention to the distribution of the cellular adhesion molecules { namely E-selectin, ICAM-1 and molecule adhesion of the cell membranes }, chemo (IL-8) and tissue degradation { metalloproteinase matrix (MMP) 1 and 3 }.

Remsima powder is an intravenously treated biosimilar substance used in infusion concentration (Remsima IV or CT-P13 IV). For the reference medication, there are no other licensed medical outlets or administrative directions.The MAH is demanding a new Remsima formulation, expected to be provided as a subcutaneous injection (henceforth Remsima SC or CT-P13 SC). During the drug development program, the Remsima SC formulation was used and the same formulation is used for the commercial device. In CT-P13 1.9, PK of infliximab was shown to be similar following SC injection with the pre-filled syringe and autoinjector.

Depending on pharmacokinetic research of adult patients, dose-independent distribution at a steady-state specified that infliximab was primarily dispersed within the vascular compartment. Infliximab's mean terminal half-life is 7.7-9.5 days. The research was based on a single dose of infliximab given to a pharmacokinetic sample of patients with Crohn's disease, plaque psoriasis and rheumatoid arthritis.

Although positive reports that indicate inherent genotoxic characteristics of a drug, sufficient in vivo results are often used to assess the biological importance of these in vitro signals. However, since various indirect pathways for genotoxicity operate only above certain thresholds, a safe limit (threshold) for drug classes that have evidence for this could also be identified.

In order to find potential threats such as carcinogenicity, genotoxicity, and reprotoxicity the International Council for Harmonization of Technical Standards for Human Usage (ICH), was established as a full set of health policies.  New advances have been made in the non-clinical test strategy to assess the QT interval prolongation liability, which is the leading cause of pharmaceutical withdrawal in recent years. S2 genotoxicity experiments and S4 toxicity monitoring are the two recommendations chosen.

The objective of this guidance is to study the micro-molecules in the drug components and this guidance is not applicable to the biologics. The ICH M3 (R2) guidance provides details regarding the time frame of the studies related to the clinical development. Genotoxicity tests are characterized as an in vitro and in vivo tests formed in order to identify compounds that prompt genetic harm by different procedures. These tests are able to identify hazards with respect to damage to DNA and its fixation.

A detailed evaluation of the genotoxic capacity of the medication substance is mandatory for the registration process. Some studies have shown that many mutagenic compounds are rodent carcinogens in the reverse bacterial mutation (Ames) test. The addition of in vitro mammalian testing enhances the sensitivity to the identification of carcinogens by rodents and expands the spectrum of genetic events recognized, while reducing the predictive specificity; thus enhancing the frequency and non-carcinogenicity of positive results. But perhaps a battery approach is of great importance, as there is hardly any study able to identify all the tumor-relevant genotoxic procedures.

Ankylosing Spondylitis (Bechterew’s disease)

Evaluation of mutagenicity in the bacterial reverse gene mutation trial is the specific features of standard test battery. This study was seen to identify important genetic alterations and most of the genotoxic rodent and carcinogens in humans.

The following should also be assessed for genotoxicity in mammalian cells in vitro and/or in vivo.

Comparative analysis has shown that each in-vitro testing system provides false negative and false-positive results in relation to the estimation of rodent carcinogenicity. The carcinogens are identified mainly by genotoxicity batteries (in vitro and in vivo) which are intended to work by a process involving direct genetic disruption, for example the most known human carcinogenes. It is therefore not known that non-genotoxic carcinogenes are detected by these batteries. Experimental factors, such as the limited capacity of metabolic activation systems in vitro, may lead in in vitro experiments to false negative outcomes. The research battery method to substances with genotoxic properties is intended to lessen the risk of false negative results.

The aim of this guideline is to define the factors that exist in the health evaluation of a medicinal substance to chronic toxicity research in rodents and non-rodents. Because the direction is not legally binding, a claimant may provide an alternative approach with rationale. The guideline was designed with the exception of those previously covered by ICH Guideline for health trials of biotechnological items, such as monoclonal antibodies, and recombinant DNA proteins. This guidance was used to manufacture pharmaceutical materials. During a first International Conference on Harmonization in 1991, the methods for assessing persistent toxicity in the 3 regions (EU, Japan and the United States) were discussed. As a consequence, a scientific consensus on the methodology to continuous rodent research has been established to promote a harmonized6-month surveillance cycle. However, the chronic toxicity monitoring of non-rodents has been subject to different approaches over the length of the study. Due to the absence of a harmonized period, pharmaceuticals companies needed to carry out partially duplicated trials for six months and 12 months for the development of new medicines. While ICH's goal is to reduce or remove the need for re-investment in science during the production of pharmaceutical drugs and to allow the use of materials, animal and human capital more effective while preserving protections that preserve public health additional scientific reviews have been carried out.

The responsible officials in the three areas carried out this review as a joint exercise. For 12 months, but not more than 6 months, there have been results in a number of cases. It was determined that this was detected in a nine-month study or could have been done. Testing for 12 months is typically incomplete and for less than 9 months, testing may be adequate. Under Council Directive 75/318/EEC as amended, non-rodent studies lasting 6 months in the EU are acceptable. A 6-month research would not be required to avoid replication of experiments with a longer duration.

Based on the extensive analysis and evaluation of the listed results in nonrodents and based on accomplishments of ICH1 with respect to rodent research and in order to avoid duplication the following experiments are considered acceptable for submission in the 3 Regions and pursue a common development plan on the chronic toxicity testing of new drug products:

Rodents - a study of 6 months duration

Non-rodents - a study of nine months duration.

References

European Medicines Agency 2020. Annex i Summary Of Product Characteristics. Ema.Europa.Eu. Available At: Https://Www.Ema.Europa.Eu/En/Documents/Product-Information/Remsima-Epar-Product-Information_En.Pdf [Accessed 11 Jan. 2020].

Gheorghe, c., Svoboda, p., Dimitriu, a., Mateescu, b. And Kotzev, i., 2018. p420 Effectiveness And Safety Of Biosimilar Infliximab (Remsima) In a Real-Life Setting In 84 Patients With Crohn’s Disease And Ulcerative Colitis. Journal Of Crohn's And Colitis, 12(Supplement_1), Pp.s316-s317.

Guerra Veloz, m.f., Arguelles Arias, f., Perea Amarillo, r., Castro Laria, l., Perez, m., Benítezroldán, a., Merino, v., Ramirez, g., Vilches Arenas, a. And Caunedo Alvarez, a., 2016, March. Safety And Efficacy Of Infliximab Biosimilar (Remsima (c)) In Crohn's Disease Patients In Clinical Practice: Results After 6 Months Of Treatment. In Journal Of Crohns & Colitis (Vol. 10, Pp. s328-s329). Great Clarendon St, Oxford Ox2 6dp, England: Oxford Univ Press.

Jahnsen, j. And Jørgensen, k.k., 2017. Experience With Biosimilar Infliximab (Remsima®) In Norway. Digestive Diseases, 35(1-2), Pp.83-90.

Jahnsen, j., 2016. Clinical Experience With Infliximab Biosimilarremsima (Ct-p13) In Inflammatory Bowel Disease Patients. Therapeutic Advances In Gastroenterology, 9(3), Pp.322-329.

Jung, s.k., Lee, k.h., Jeon, j.w., Lee, j.w., Kwon, b.o., Kim, y.j., Bae, j.s., Kim, d.i., Lee, s.y. And Chang, s.j., 2014, September.Physicochemical Characterization Of Remsima®.In Mabs (Vol. 6, No. 5, Pp. 1163-1177).Taylor & Francis.

Yoo, d.h., Prodanovic, n., Jaworski, j., Miranda, p., Ramiterre, e., Lanzon, a., Baranauskaite, a., Wiland, p., Abud-Mendoza, c., Oparanov, b. And Smiyan, s., 2017. Efficacy And Safety Of Ct-p13 (Biosimilar Infliximab) In Patients With Rheumatoid Arthritis: Comparison Between Switching From Reference Infliximab To Ct-p13 And Continuing Ct-p13 In The Planetra Extension Study. Annals Of The Rheumatic Diseases, 76(2), Pp.355-363.