Acute ulcerative colitis and Crohn's disease are the main diseases in the category of inflammatory bowel chronic diseases which vary in the location of the bowel and severity. This report describes the several physical and chemical properties of two chosen drugs, pharmacology and clinical use, formulation, manufacturing and regulatory issues. These drugs are prednisolone (synthetic) and adalimumab (biotechnology), which are for the treatment of refractory or moderate IBD as adjunctive therapy and severe Cronh's Disease when conventional therapy has not responded satisfactorily or due to contraindications or intolerance.
Crohn's disease is an autoimmune disorder characterized by a chronic inflammation in the gastrointestinal tract, affecting any area of it and the intestinal wall becomes thick due to the inflammation. This autoimmune disorder has period of times when patient's condition is controlled without symptoms well known as remission, and relapse is when the disease is active and the patient has symptoms such as abdominal pain, diarrhea ( with mucus or blood), fever, weight loss, bleeding from the rectum, tiredness, among others.
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In the UK, the prevalence of Crohn's disease is estimated to be about 50-100 per 100,000 people, affecting approximately 60,000Â people in the UK. The incidence is greatest in people aged between 15 and 30Â years although it may affect people of any age. Mortality among people with Crohn's disease is only slightly higher than in the general population. (http://www.nice.org.uk/guidance/index.jsp?action=article&o=46234)
Adalimumab is a recombinant human immunoglobulin
Physical and Biological Properties
HumiraÂ® (adalimumab) is presented as a pre-filled pen or a syringe, containing a colorless and clear solution with a pH about 5.2.
This drug is composed of two kappa light chains and two IgG1 heavy chains. The light chains have a molecular weight of around 24 kDa and the heavy chains with a molecular weight of about 49 kDa, resulting in a total weight of 148 kDa
Protein Chemical Formula: C6428H9912N1694O1987S46
Protein Average Weight: 144190.3000
Pharmacological and clinical use
Before going deeply in the pharmacological use, it is relevant to mention briefly about the cytokine TNF. 'The tumour necrosis factor family of cytokines essentially consists of two related regulatory factors: TNF-Î± (cachectin) and TNF-Î² (lymphotoxin)' (Walsh, Biopharmaceuticals: Biochemistry and Biotechnology, p 255 - 260). Even though both molecules are bound the same receptor and the induction of biological activities is very similar, their similarities in acid nucleic sequence and organization is limited. Sometimes, TNF-Î± is referred to TNF and has a wide research than TNF-Î².
Adalimumab targets a protein in the body called TNF-alpha (tumour necrosis factor-alpha). TNF-alpha is produced naturally by the body, as part of its immune response, to help fight infections, temporarily causing inflammation in affected areas. When the body produces in excess amount TNF-alpha is called Crohn's Disease. By blocking TNF-alpha, adalimumab reduces inflammation and relieves the symptoms of Crohn's Disease. (Crohn's and Colitis UK Drug Treatment Information).
Indication: It is considered as a second line systemic therapy for the treatment of Crohn's disease in patients have no responded to other therapies (e.g. corticosteroids and/or immunosuppressant) or who are intolerant to or have medical contraindication for such therapies.
Dose and Route of Administration: It is administered by subcutaneous injection. Most monoclonal antibodies are by subcutaneous via due to the oral bioavailability is low for two reasons:
The degradation of proteins in the gastrointestinal tract
Poor permeability of the wall
The dose of adalimumab is as follow:
Week 0: the patient is given 80 mg of HumiraÂ®
Week 2: the patient is given 40 mg of HumiraÂ®
After the second week, the dose is every other week with 40 mg
Depending on the response, it may be needed to increase the dose every week (40 mg)
For a more rapid response, it may be need to administrate 160 mg on week 0 followed by 80 mg on week 2 and then 40 mg every other week.
Mechanism of Action: TNF plays an important role in regulating inflammation and immune response
'Adalimumab binds specifically to TNF-alpha and blocks its interaction with the p55 and p75 cell surface TNF receptors' (http://www.medicines.org.uk/emc/document.aspx?documentId=21201, March 3rd, 2011).
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There is a decrease in levels of C-reactive protein (CRP) levels 'as well as a reduction of the number of cells expressing inflammatory markers in the colon including a significant reduction of expression of TNF-Î±' (http://www.medicines.org.uk/emc/document.aspx?documentId=21201, April 6th, 2011).
After a 40 mg subcutaneous administration of Adalimumab, the absorption and distribution is reached 5 days after the administration.
The absolute bioavailability is a study performed to compare when the drug is reached in the systemic circulation between non-intravenous administration, in this case subcutaneous, and intravenous administration. The three studies showed an estimated of the average absolute bioavailability of 64 % in subcutaneous via and by intravenous system there was a proportional dose in the concentrations. The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies (ref).
Based on clinical trials, it was found that 7 subjects out of 269 had human adalimumab against antibodies (AAA); as a result, there was an increase of clearance and reduction of efficacy of the drug. 'There is no apparent correlation between the presence of anti-adalimumab antibodies and the occurrence of adverse events' (http://www.medicines.org.uk/emc/document.aspx?documentId=21201, April 6th, 2011).
Warnings and Precautions
There exists a potential risk of getting infections due to the administration of anti-TNF-Î± antibodies compromises the body's capability of fighting against pathogens. The cytokine (TNFÎ±) is produced by monocytes (sort of white blood cells) that play a pivotal role in immune response and inflammation signals.
Contraindications: Hypersensitivity to the drug substance or to any of the excipients; active tuberculosis or other severe infection such as sepsis and opportunistic infections and moderate to severe heart failure.
Anakinra: The use concomitant of this drug along with another TNF-blocking agent has a high risk in the development of serious infections and also a neutropenia's risk.
Live vaccines. After the administration of adalimumab, the immune system is diminished and if it is administrated a live vaccine the body is overburden leading to a reduction of the efficacy of the vaccine and the patient may have an infection.
Methotrexate: This drug has a good interaction with adalimumab since it reduces the formation of AAA, reduce clearance and increase the efficacy.
Pregnancy and Lactation: There is not data available for pregnancies. Regarding lactation, 'it is not known whether adalimumab is excreted in human milk or absorbed systemically after ingestion'. However, women must not breast-feed since human immunoglobulins are excreted in milk.
Infections and Infestations: respiratory tract infections, systemic infections, intestinal infections, Oral infections, etc
Neoplasms benign, malignant and unspecified: benign neoplasm, lymphoma.
Blood and the lymphatic system disorders: leucopaenia, anaemia, leococytosis,
Immune system disorders: hypersensitivity, allergies
Psychiatric disorders: mood alterations, anxiety, insomnia.
Eye disorders: visual impairment, conjunctivitis, eye swelling
Cardiac disorders: tachycardia, arrhythmia, congestive heart failure
Skin and subcutaneous tissue disorders: rash, pruritus, urticaria, dermatitis, scar
Renal and urinary disorders: haematuria, renal impairment, nocturia
Production of the active substance
'The active ingredient is produced by cell culture using Chinese Hamster Ovary (CHO) cells in media with no human or animal derived components' (EMEA). Expansion of the CHO cell culture from a single vial of the WCB is accomplished by sub-cloning into spinner flasks of increasing size (re-phrase). The spinner flask has the propriety of facilitate the production of cell. Once it reaches an appropriate level of inoculation, cells are transported to the seed fermentor for the final expansion before seeding the production bioreactor. After an additional cultivation, production medium is added to increase the culture volume to final batch size. (rephrase)
The purification of adalimumab is carried out through various chromatography steps with a low pH treatment and nanofiltration for virus inactivation and removal. The objective of performing the purification is to minimize the presence of non-human substances.
Why nano filtration??
Manufacturing of the finished product
Quali - Quantitative Formula
Each prefilled syringe delivers 0.8 mL which contains
monobasic sodium phosphate dydrate
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dibasic sodium phosphate dehydrate
citric acid monohydrate
minimise the formation of aggregates
added as necessary to adjust pH.
water for injection
c.s.p 0.80 mL
Storage and Stability of the finished product
Adalimumab must be refrigerated at 2 - 8 °C. Shelf Life 24 months
Marketing Authorization Procedure
In order to grant the marketing authorization, the pharmaceutical company must submit an application with all the supporting documentation. Please refer appendix 1 for further details of the documentation needed.
Because adalimumab is a biotechnological product, it was evaluated under the centralized procedure which is compulsory for products of this category and it is valid through the EU. The application procedure is carried out as follows:
EMEA staff does a prior evaluation to check if it is complete and comply the EU guidelines in a period of 10 days. If the application is acceptable, then it is given a filing date when it is legally accepted.
The evaluation time of the dossier is 210 days
The pharmaceutical company or sponsor pays the fee which is about £ 200.000
Two rapporteurs are selected to assess the application by their respective National Health Authority and one is chosen by the sponsor. However, the CPMP is the responsible for giving the final approval. This opinion is informed to EMEA who have 90 days to deliberate it.
EMEA issues the marketing authorization which is valid for 5 years
Legal Class: This is classified as a POM (Prescription Only Medicines).
Advertising and promotion
Related to advertising and promotion and according to the blue guide, this drug has some restrictions, for example, it cannot be promote to the public and on web sites only if the advertisement can be seen by Health Professionals.
Risk Management Plan
'A risk management system is a set of pharmacovigilance activities and interventions designed to identify, characterize, prevent or minimize risks relating to medicinal products, including the assessment of the effectiveness of those interventions' (http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004888.pdf, 28th March, 2011).
In other words, this report summarizes all activities that MAH must carry out to follow up the safety and efficacy and which must be submitted to the health authority and should be submitted in the marketing application and post-marketing The RMP is based on the adverse effects found through pharmacovigilance, indicating the commitments and warnings which must be updated on the Summary Product of Characteristics in order to comply with the regulations.
This is required along with the application for new products for:
A New Chemical Entity
A biological product
When it is required safety concern for generic products with reference medicinal product