Biologics

Question 1

Draw the structure of an antibody and label it?

Answer 1

Antigen binding site
Constant/Variable regions
Heavy and light chains
Y shaped structure

Question 2

What is the difference between murine, chimeric and humanised antibodies?

Answer 2

The main difference between these types of antibodies lies in their composition and degree of similarity to human antibodies. Murine antibodies are fully derived from mice and are the most different from human antibodies. Chimeric antibodies have a mix of mouse and human components, while humanized antibodies are mostly human with only the specific binding regions derived from mice.

Each type of antibody has its advantages and disadvantages depending on the intended use. Researchers and clinicians choose the appropriate type based on factors such as efficacy, safety, and potential immune responses in humans.

AI:

Murine, chimeric, and humanized antibodies are all different types of antibodies used in medical research and therapy. Let me explain each one to you:

1. Murine Antibodies: Murine antibodies, also known as mouse antibodies, are antibodies that are originally derived from mice. These antibodies are made by immunizing mice with a specific antigen, which stimulates the mouse immune system to produce antibodies against that antigen. Murine antibodies have a high affinity and specificity for their target antigen. However, when used in humans, they can sometimes elicit an immune response because the human immune system recognizes them as foreign.
2. Chimeric Antibodies: Chimeric antibodies are a type of antibody that is created by combining parts of a mouse antibody with parts of a human antibody. The variable region, which is responsible for binding to the target antigen, is derived from the mouse antibody, while the constant region, which is responsible for other functions of the antibody, is derived from a human antibody. This combination reduces the immunogenicity of the antibody in humans, making it less likely to trigger an immune response.
3. Humanized Antibodies: Humanized antibodies are antibodies that have been engineered to be more similar to human antibodies. They are created by grafting the complementarity-determining regions (CDRs), which are the specific binding regions of the antibody, from a mouse antibody onto a human antibody framework. This process preserves the specificity of the mouse antibody while minimizing the immunogenicity in humans. Humanized antibodies are designed to be even more similar to human antibodies than chimeric antibodies.

The main difference between these types of antibodies lies in their composition and degree of similarity to human antibodies. Murine antibodies are fully derived from mice and are the most different from human antibodies. Chimeric antibodies have a mix of mouse and human components, while humanized antibodies are mostly human with only the specific binding regions derived from mice.

Each type of antibody has its advantages and disadvantages depending on the intended use. Researchers and clinicians choose the appropriate type based on factors such as efficacy, safety, and potential immune responses in humans.

Question 3

Naming of monoclonal antibodies?

Answer 3

All monoclonal antibodies have the MAB suffix in their name and before MAB the letter reveals the cell origin:

U: human
O: mouse
Xi: chimeric
Zu: humanised
Xi-Zu: hybrid of chimeric and humanised

Disease target can also be included in the name:

Im: immune
Es: infectious diseases
Vir: viral
Mel: melanoma
Col: colon

Question 4

Give examples of monoclonal antibody drugs and their role?

Answer 4

1-Anti-IL6: Tocilizumab an interleukin-6 inhibitor blocks or bind to the IL-6 receptor that prevents IL-6 being from able to bind to it is receptor therefore blocking the response to IL-6.

2-Anti-CD20: Rituximab chimeric monoclonal antibody it binds to an antigen present on the surface of
B-cell. This CD20 antigen is present on early B cells a.i. Pre-B-lymphocytes and mature B lymphocytes CD20 portion B-cell. By blocking or binding to CD20 antigen Rituximab can lead to B-cell depletion

3- Anti-costimulation: Abatacept is a recombinant fusion protein that inhibits co-stimulatory signals essential for T-cells activation.
These are biologics that are called fusion proteins so recombinant proteins that have been fused with either parts of an antibody. Abatcept has the constant region of an antibody but the top part is recombinant protein.

Abatacept blocks the interaction between an antigen presenting cell and a T-cell. In order for T-cell to become activated on APC it will use a T-cell receptor to interact with an antigen that is expressed by an APC via the MHC class but it needs a second co-stimulatory signal, works by binding and blocking the antigens on APC cells to prevent that co-stimulators signal and subsequently prevent T-cells activation.

Question 5

Anti-TNF strategies

Answer 5

Anti-TNF has numerous functions within inflammatory conditions.

To function TNF will bind to a TNF receptor on a range of different cell types. TNF will either bind to TNF receptor 1 or 2, these receptors are present on different cells and have different signalling pathways.

There is a massive family of TNF receptors and may have death domains that lead to apoptosis.
Anti-TNF is a strategise has a big role in inflammatory/autoimmune diseases.

As TNF can be a differentiation factor for monocytes to macrophages

TNF important cytokine inducing mounting a Defense against intracellular pathogens that have been engulfed.

TNF is a growth factor for both T and B Cells as they grow and go through different maturation phases.

Plays a massive role in haemotopoiesis so determining cells going from those early precursors into the more differentiated cell types. TNF signalling through that pathway it can induce the expression of other cytokines including IL-1&6.

It drives an inflammatory process it can also be a growth factor for other cells it can have a prothrombotic action increasing platelet adhesion. It can lead to endothelial cells adhesion and if endothelial cells are activated by TNF they will present on their cell surface a range of molecules different adhesion molecules vcam Icam and this allows endothelial cells to interact with leukocytes in the blood once interaction happens it allows immune cells extravasate from being the blood to being in the endothelial cells and into localised tissues as a result TNF is a major target in inflammatory diseases.

AI:

Wow, that’s a lot of information! Let me break it down for you.

There is a molecule called TNF (tumor necrosis factor) that has many important functions in our body, especially in inflammatory conditions. TNF can bind to different types of receptors called TNF receptor 1 and TNF receptor 2. These receptors are found on different cells in our body and they have different ways of sending signals.

TNF can also be a factor that helps certain cells in our body, called monocytes, turn into macrophages. Macrophages are important cells that help our body defend against harmful pathogens.

TNF is also a growth factor for two types of cells in our immune system, called T cells and B cells. These cells need TNF to grow and go through different stages of development.

Another important role of TNF is in the process of making new blood cells, called hematopoiesis. It helps in the transformation of early precursors into more specialized cell types. TNF can also trigger the production of other cytokines, such as IL-1 and IL-6, which are important molecules in our immune system.

TNF can cause inflammation in our body and it can also act as a growth factor for other cells. It can increase the stickiness of platelets, which are involved in blood clotting. It can also activate endothelial cells, which line the blood vessels, causing them to express molecules that allow immune cells to stick to them. This allows immune cells to leave the blood and enter tissues where they are needed to fight infection or inflammation. Because of its role in inflammation, TNF is a major target for treating inflammatory diseases.

So, in summary, TNF has many important functions in our body, including regulating inflammation, promoting the growth and development of immune cells, and playing a role in blood cell production. That’s why scientists have developed medications called anti-TNF therapies to help treat inflammatory and autoimmune diseases.

Question 6

Give examples of anti-TNF strategies

Answer 6

1-Infliximab: Chimeric (part human part mouse cell line) anti-TNF monoclonal antibody. Given via intravenous infusion every 8weeks. Reserved for patients who are unable to self-administer subcutaneous injections.

2- Adalimumab: Anti-TNF, fully human recombinant monoclonal antibody. Send administered by subcutaneous injection

3- Etanercept: Recombinant soluble human TNF p75 receptor fusion protein consisting of two p75 receptors that are linked to the Fc portion of human immunoglobulin IgG. Self administered by subcutaneous injection.

4- Certolizumab pegol: TNF-alpha specific Fab fragment of a humanised monoclonal antibody, self administered by subcutaneous injection.

Question 7

What is a Biosimillar?

Answer 7

A biosimilar is a biological product that is highly similar to and has no clinically meaningful difference from an existing FDA approved product.

There are multiple anti-TNF antibodies depending on those subtle differences in the variable region of an antibody that allows it to bind to the antigen.

There is a range of different biosmiliars for each monoclonal antibodies.

Question 8

Summary

Answer 8

we were looking very much at different antibodies and the naming of antibodies and some examples of antibodies as biologics we were also looking at TNF alpha and targets of anti TNF alpha therapy and how TNF alpha is very prominent in terms of inflammatory conditions as a target

Question 9

Pharmacology of IL-6 and JAK inhibitors?

Answer 9

Interleukin-6 (IL-6) plays a significant role in the pathogenesis of rheumatoid arthritis by contributing to inflammation and joint damage. Targeting IL-6 with biologics like tocilizumab, an IL-6 receptor antagonist, has shown efficacy in managing RA symptoms by dampening the inflammatory response mediated by IL-6.

On the other hand, JAK inhibitors, such as Tofacitinib and Baricitinib, work by inhibiting Janus kinases, which are essential proteins associated with specific receptors in the JAK-STAT pathway. By blocking JAK proteins, these inhibitors disrupt cytokine signaling and modulate the inflammatory cascade involved in RA. This targeted approach allows for a broader inhibition of multiple cytokines, offering a more comprehensive strategy to manage inflammation in patients with rheumatoid arthritis.

AI:

It’s fascinating to delve into the intricate pathways and biologics involved in the context of rheumatoid arthritis. Understanding the pathogenesis of RA is crucial as we transition into exploring the clinical aspects from diagnosis to treatment.

The significance of targeting specific signaling pathways like interleukin-1 and interleukin-6 in the pathogenesis of RA cannot be overstated. Biologics such as anakinra and tocilizumab, which act as interleukin receptor antagonists, play a pivotal role in blocking these signaling pathways.

Moreover, therapies like Rituximab for B cell depletion and abatacept for blocking costimulatory signals have shown promise in the treatment of RA by targeting different mechanisms of the disease.

The emergence of JAK inhibitors like Tofacitinib and Baricitinib presents a new frontier in RA treatment. By inhibiting Janus kinases associated with specific receptors, these inhibitors disrupt cytokine signaling through the JAK-STAT pathway, leading to the modulation of the inflammatory response. This approach allows for the inhibition of multiple cytokines associated with different JAK families, offering a more comprehensive strategy to mitigate inflammation in RA patients.

Slide:

we now need to think of these biological pathways and the biologics that target them in the context of conditions and in this first instance thinking about rheumatoid arthritis so you have done some work now on autoimmune diseases how the pathogenesis of rheumatoid arthritis and you’re going to be moving into thinking about the clinical aspects from diagnosis to treatment.

now what you need to understand and appreciate is that these different signalling pathways that we’re talking about here in this diagram are targets of therapies but also understand why is this target so you have learnt about interleukin-1 interleukin-6 and as being prominent in the pathogenesis of RA you should have that understanding

There are biological therapies that target these so anakinra as a interleukin 1 receptor antagonist and in terms of an antibody therapy tocilizumab it’s an interleukin 6 receptor target so it’s blocking interleukin 6 signalling

now the reason we’re raising this, is because previously some of these agents have been used only in very severe cases of RA where other therapies have been tried and haven’t worked but more prominently now some of these biological therapies are coming into standard practise for more Moderate RA and so your awareness of these different therapies needs to be increased on your understanding of how they work

So briefly mentioned interleukin 1 and 6 we also need to understand the mechanisms behind why using Rituximab for B cell depletion would be useful in rheumatoid arthritis and also why abatacept blocking that costimulatory signal is also of benefit

secondly we need to think of other relevant agents and a little bit about the background in terms of the pharmacology of the signalling of these so relatively new type of medicine is Tofacitinib and Baricitinib and both of these are JAK inhibitors JAK stands for Janus kinases and these are proteins that associate with specific receptors in this case we’re thinking about receptor Tyrosine kinases
those types of receptors now when you have growth factor of cytokines signalling a number of these different cytokine signal through the JAK STAT pathway which means their tyrosine kinase receptors come together and they’re associated with JAK proteins once the receptors ligand binds the JAK that are associated can also phosphorylate the receptor and then these phosphorylation sites become a beacon to attract other proteins such as STATS that help relay that message and that signal to the nucleus and therefore activate the transcription of a wide number of other genes and in this case we’ve got cytokine signalling the transcription of other cytokines and through that the production and release and perpetuation of that inflammatory response.

so you need to know that we now have different JAK inhibitors used in therapy for rheumatoid arthritis for patients and these JAK inhibitors will work through inhibiting that JAK protein that’s associated with the receptor this means a couple of things so it means that rather than just inhibiting one cytokine each there’s different families of JAK
that each family will associate with receptors that signal through different cytokines so there are different sites can families that signal through the same JAK and so by inhibiting that JAK you’ll then preventing cytokine signalling from a range of cytokines rather than just interleukin-6 on its own for example, so this is another method that we can use to dampen down the inflammatory response.

Question 10

What’s the EMA guidance on biologics?

Answer 10

• EMA’s human medicines committee (CHMP) endorsed measures recommended by PRAC to minimize risks with Janus kinase (JAK) inhibitors for chronic inflammatory disorders.
• Risks associated with JAK inhibitors include cardiovascular conditions, blood clots, cancer, and serious infections.
• JAK inhibitors should be reserved for patients aged 65 years or older, those at increased risk of major cardiovascular problems, smokers, and those at increased risk of cancer when no suitable alternatives are available.
• Caution should be exercised in patients with risk factors for venous thromboembolism (VTE) and doses should be reduced in certain patient groups at risk of VTE, cancer, or major cardiovascular problems.
• Safety findings apply to all approved uses of JAK inhibitors in chronic inflammatory disorders.
• Product information will be updated with new recommendations and warnings, and educational materials will be revised accordingly.
• Patients should be vigilant for symptoms like chest pain, shortness of breath, and skin abnormalities, and should consult their doctor promptly.
• Healthcare professionals should discuss risks associated with JAK inhibitors with patients and carry out periodic skin examinations.
• Certain patients should only be prescribed JAK inhibitors if no suitable alternatives exist, and cautious use is recommended in others.
• A letter will be sent to healthcare professionals informing them of the review outcome and updated treatment recommendations.
• JAK inhibitors subject to review include Cibinqo, Jyseleca, Olumiant, Rinvoq, and Xeljanz, used to treat various chronic inflammatory disorders by blocking Janus kinases.
• The review did not cover certain JAK inhibitors used for myeloproliferative disorders or the short-term use of Olumiant in COVID-19 treatment.

Question 11

Biologics drug therapeutics
Learning objectives?

Answer 11

Describe the therapeutics of key medicines involved in the management of immune diseases.

Use of biologics for the treatment of any condition is an extremely specialised area of pharmacy usually managed in the secondary care setting although medication may be administered in the primary care setting

for this reason regimes and reasons for using one agent over another is outside the scope of this screencast instead the screencast is to provide important key points about biological agents used in treatment and to make you aware of some common drug characteristics that you may encounter both in general primary and secondary care

Question 12

List and name the Anti-TNF drugs?

Answer 12

Adalimumab
Certolizumab pegol
Etancerpt
Golimumab
Infliximab

Question 13

List the IL-6 inhibitors, the anti B-cell and anti T-cell?
List the JAK inhibitors?

Answer 13

IL-6 Tocilizumab
Anti-B-cell Rituximab
Anti-T-cell Abatacept

JAK inhibitors:
Tofacitinib
Baricitinib

Question 14

Give an overview of the commonly used biologic agents?

Answer 14

• Commonly used biological agents in the treatment of immune diseases:
  • Anti-TNF or TNF inhibitors
  • Interleukin-6 receptor inhibitors
  • Anti B-cell drugs
  • Anti T-cell drugs
• Focus on TNF inhibitors, particularly infliximab
• Newer targeted therapies:
  
  • JAK inhibitors
  • Small molecules targeting the JAK-STAT pathway
• JAK inhibitors are used in conditions like rheumatoid arthritis
  
  • Specialized use, refer to specific lectures for more information
• MHRA advice in March 2020:
  
  • Increased risk of venous thromboembolism with baricitinib and tofacitinib
  • Consider patient’s risk factors for VTE before initiating these drugs
• Refer to BNF or SPC for further information

an overview of some commonly used biological agents used in the treatment of immune disease you have the anti-TNF or TNF inhibitors interleukin 6 receptor inhibitors, the anti B-cell and the anti T-cell drugs we’re going to concentrate on TNF inhibitors particularly infliximab.

there are also newer agents which are not biological agents but are targeted therapies and these at the moment are being used in conditions such as rheumatoid arthritis so these are the JAK inhibitors so these are small molecules targeting the JAK STAT pathway they use is extremely specialised please refer to the rheumatoid arthritis lectures which gives you an idea of where they fit into the treatment pathway and if you do require any further information about them you can refer to the BNF or the SPC

However, I would like to highlight a couple of important things about them in March 2020 the MHRA released some advice about the increased risk or venous thromboembolism with these agents; baricitinib and tofacitinib therefore it’s important to consider a patient’s risk factors for venous thromboembolism if considering initiation of either of these drugs

Tofacitinib also has some significant interactions for example when it’s used with moderate CYP 453A4 or potent CYP452C19 inhibitors the dose of Tofacitinib should be reduced.

Question 15

What considerations are taken when initiating biologics?

Answer 15

*Increased risk of infection: considerations required around surgery

*Potential increased risk of malignancy

*Potential increased risk to patients with cardiac failure (class III or IV)
TNF inhibitors

*Use of alcohol
No problems within normal limits (however may need reduction/cessation due to concomitant DMARDs)

General points around biologics as with all the specialist drugs discussed the use of treatment in patients with immune diseases, biologics should be prescribed by a physician appropriately trained in prescribing them and have an an appropriate monitoring plan in place with specialist knowledge of the drugs and how they should be managed initiation should be a joint consideration between the patient and the prescriber and the patient should be appropriately educated to their use especially when you consider the potential risks and side effects and other issues.

It is important to consider the increased risk of infection with biological agents we’ll start off by considering the anti TNF inhibitors so we know that TNF inhibits inflammation and also modulate cellular immune responses hence is used in immune diseases but is also needed to clear intracellular infections therefore host defences compromised when it is used increasing their risk of infection trivial infections may last longer and more serious infections may develop. these can include bacterial infections and be a severe sepsis it may also include invasive fungal infections viral infections and other opportunistic infections that have been observed in patients some of these may be fatal conventional DMARDs can increase the risk of infection as can some of the conditions that they’re being used to treat such as rheumatoid arthritis however the use of anti TNF inhibitors is thought to increase the risk of serious infection by approximately 20% and it may also be the case that some signs of infection such as fever may be masked by using the biological agent this information as you will see means that medicines should not be started in those with severe infection and for patients that develop infection they should be closely monitored and have complete diagnostic evaluation of the infection that means to find out exactly its source and the infective agent anti TNF therapies may need to be stopped dependent on the severity of the infection and the patient should receive appropriate treatment for the infection reducing the risk of infection is important for example ensuring patients are up to date with their vaccinations before initiation of the biological therapy and that they receive the annual influenza and the one off pneumoccocal vaccine will also reduce their risk
these are inactivated vaccines and are safe in patients on biologics

live vaccines should be avoided during treatment ensuring patients also do not come into contact with individuals with infections such as chicken pox or shingles and that if these patients do come into contact with somebody suffering with these conditions that they seek help because it may well be that they need a course of treatment to prevent severe infection in the patient receiving the biological agents patients over 50 should be given the herpes zoster vaccination assuming there’s no contraindications to it before initiation of the biological agent it needs to happen before because this is a live attenuated vaccine which cannot be given when the patient starts therapy and patients that have not had chickenpox should have the varicella zoster vaccine before commencing their biological agents patients due for surgery are likely to have their TNF inhibitors stopped beforehand to reduce the risk associated with infection the risk is increased by surgery itself and can be further increased by use of the drug all of the information I’ve just given you relate specifically to TNF inhibitors this is because there is significant evidence around the use of TNF inhibitors there are comparatively few studies that have looked at non TNF inhibitor biologics therefore this guidance currently encompasses that group of medicines also it is also assumed that they are at increased risk of infection and the same precautions still apply

another general point related to biological agents is that patients using them potentially have an increased risk of malignancy TNF is important in the body’s defence against cancer therefore there is the theoretical possibility of an increased chance of developing cancer went on an anti TNF agent many years of use of the TNF inhibitors there have been isolated reports but not firm and consistent evidence of cancer long term follow-up of patients is continuing and is done by a number of disease registries that follow the progress of a patients for example with rheumatoid arthritis or other conditions on biological agents caution is required As for some diseases it is also known that they can increase the risk of malignancy for example in rheumatoid arthritis
general guidance is that biologics should not be used in those with clinical signs of malignancy r that are under investigation for malignancy patient started on therapy should be informed that ongoing vigilance is important similarly patients should be warned to self monitor and protect themselves from skin cancers as information regarding the incidence of this impatience with biologics is also inconsistent this applies to both TNF inhibitors and non TNF biological agents

however in the non TNF inhibitor group so any medications that are not TNF inhibiters but are biologic there appears to be a lower incidence of malignancy with these patients another general point for TNF inhibitors is the potential increased risk patients with cardiac failure in terms of increasing their severity of symptoms although data is reassuring it is still important to be cautious
TNF is increased in those with cardiac failure compared to the general population and trials of using certain TNF inhibitors in the treatment of heart failure actually showed a worsening of a patients heart failure this effect does not appear to be a problem with non TNF inhibitors finally TNF inhibitors should be used with caution in those patients with demyelinating diseases such as multiple sclerosis as they are known to worsen the symptoms of these conditions

general use regarding the use of alcohol in patients on biological agents is that alcohol may be consumed within normal limits however often these patients are on other agents for which alcohol consumption would be cautioned or should be avoided for example other DMARDs

AI:

1- Increased risk of infection with biological agents:
- TNF inhibitors inhibit inflammation and modulate immune responses
- Can compromise host defenses, leading to increased risk of infection
- Trivial infections may last longer, serious infections may develop
- Includes bacterial, fungal, viral, and opportunistic infections
- Risk of serious infection increased by approximately 20% with anti-TNF inhibitors
- Signs of infection like fever may be masked by biological agents
- Medicines should not be started in severe infection, close monitoring required
- Complete diagnostic evaluation of infection needed
- Vaccinations before initiation of biological therapy can reduce infection risk
- Avoid live vaccines during treatment
- Patients over 50 should receive herpes zoster vaccination
- Surgery patients likely to have TNF inhibitors stopped before surgery
- Caution required for infections with biological agents

2- Increased risk of malignancy with biological agents:
- TNF important in defense against cancer
- Theoretical possibility of increased cancer risk with anti-TNF agents
- Long-term follow-up ongoing, caution required
- Biologics should not be used in those with clinical signs of malignancy
- Increased risk of malignancy in some diseases, caution needed

3- Cardiac considerations with TNF inhibitors:
- Potential increased risk in patients with cardiac failure
- Data reassuring but caution advised
- Worsening of heart failure seen with certain TNF inhibitors
- Non-TNF inhibitors do not have the same effect

4- Use of alcohol with biological agents:
- Alcohol may be consumed within normal limits
- Caution with other agents that interact with alcohol

Question 16

Monitoring of biologics?

Answer 16

Monitor for:
Co-morbidities
Full blood count
Renal function eGFR, Cr
Liver function tests (LFT’s, AST, ALT and albumin)
Test for Tuberculosis
Hepatitis screen (B and C)
Chest x-ray
Ongoing therapy should be reviewed at least every 6-months

some general points in relation to monitoring of biological agents is monitoring should occur before initiation and we’ll have a look at the reasons for that and during ongoing therapy all patients should be assessed for their comorbidities prior to initiation this will include a review of the patients presence of infection or the risk of infection as well as risk factors for any other potential adverse effects caused by biologic for example a patient with co-morbidities such as COPD or interstitial lung disease or renal failure are associated with for example higher risk of infection

generally biologic should not be started in patients with serious active infection and serious active infection would be defined as those that require antibiotics or hospitalisation we would check a patient’s full blood count their renal function their liver function test
we would also test them for certain infections so for example tuberculosis the reason for this is that TB should be treated or if a patient has latent TB they should receive chemo prophylaxis prior to initiation of their biological agents as biologics have been known to cause reactivation of tuberculosis

also hepatitis screen should be undertaken for hepatitis B&C this is because there are effective treatments available that should be used prior to issue an initiation of biologics and also we should have a patient should receive a chest X-ray so these baseline tests acts as a screening tool for underlying conditions and also act as a reference point for future tests Please note that there may be some other tests that are required for specific agents for example if you were looking at a particular drug within the group of biologic there may be specific things that you would want to monitor for or you may want in a specific condition you may need to be monitoring for something and if you ever needed to know about this when you practising and there will be local guidelines and also the summary of product characteristics that would give you that information ongoing monitoring should also be undertaken and this should be at least every six months but in those patients that have a higher risk of adverse events this monitoring should take place every three months for most patients however their ongoing monitoring will fall into monitoring for other medications there on by that I mean most patients on biological agents will also be on conventional DMARDs which will have their own monitoring or requirements and as you’ve seen that monitoring is very regular where a patient isn’t on a conventional DMARD they should have a review of their full blood count renal function liver function albumin and these should occur every 3 to 6 months where biological agents are prescribed with other agents such as the conventional DMARDs it is difficult to determine the exact culprit of certain side effects

some general points regarding the pharmaceutical care of patients
patients should remain on their specific brand of treatment unless it is converted under the direction for prescriber you’ve heard of biosimilars and it’s not appropriate to convert a patient between the different agents and they should be prescribed by brands and the patient should be kept on that particular brand there are occasions when patients are converted from for example the originate a molecule to the biosimilar not least due to the cost implication and this should always be done under the guidance of the prescriber clinical physician and with appropriate monitoring as well

All patients on biological agents need to be traceable so information regarding the batch number the brand and including patients on these agents as part of a disease registry allows them to be followed up and this is essential for pharmacovigilance and when looking after patients on these agents there will be specific things that you will need to be monitoring for dependent on the agent there on and the condition they have it please in practise please refer to BNF, SPC and when working in practise your local guidance.

AI:

1- Monitoring of biological agents:
- Monitoring before initiation and during ongoing therapy
- Assess all patients for comorbidities, infection risk, and adverse effects
- Avoid starting biologics in patients with serious active infection
- Baseline tests include full blood count, renal and liver function tests, tuberculosis screening, hepatitis screen, and chest X-ray
- Ongoing monitoring every 6 months, more frequent in high-risk patients
- Consider specific monitoring for individual agents or conditions

2- Pharmaceutical care of patients on biological agents:
- Patients should remain on their specific brand of treatment unless directed by the prescriber
- Avoid converting between different agents without guidance
- Patients on biological agents should be traceable with batch numbers and brand information
- Inclusion in disease registries for pharmacovigilance is important
- Specific monitoring based on the agent and condition, refer to BNF, SPC, and local guidance for details

Question 17

Infliximab indications? Preparations? Dosing? Side effects?

Answer 17

The biological agents called infliximab and this is a TNF inhibitor it’s indicated for conditions such as rheumatoid arthritis Crohn’s disease ulcerative colitis and alkylosing spondylitis psoratic arthritis and psoriasis

Infliximab is a chimeric human murine monoclonal antibody and the preparations it’s available as or powder infusion so that would be administered via intravenous infusion and as a prefilled pen which can be given subcutaneously

These preparations are protein so they have to be injected rather than administration orally the subcutaneous injections are best for the patients because the patient would be able to do those at home however if we are needing to give the patient intravenous injection these would have to be administered in hospital

I have provided with the schedule for rheumatoid arthritis in terms of dosing just to illustrate the type of prescribing you’re unlikely to see unless you are a specialist pharmacist in this area you are more likely than to have a working knowledge of the doses if you ever faced with a prescription for infliximab you would need to clinically check it, you would be checking the doses by referring to your local monographs and guidance and you could access the SPC

In rheumatoid arthritis the clinical response is usually achieved within 12 weeks of treatment however if the desired response is not achieved then the dose may be increased in small step increments or the frequency altered to bring about the remission that you’re wanting to see with the rheumatoid arthritis
However if this doesn’t improve the situation then the biological agent should be reconsidered completely if it’s not having the effect you wanted to see so it will be removal of this agent and initiation of another treatment for the patient and you’ll see the dosing starts at week zero then Week 2 weeks 6 and then every eight weeks after that

Question 18

Route of infliximab administration and its s/e it delayed hypersensitivity?

Answer 18

Infliximab is one of those preparations which is administered by IV infusion and the infusion should be given over 2 hours and it requires 1 to 2 hours of observations by the medical staff afterwards so these patients would need to remain at the hospital setting for 1 to 2 hours after their infusion so that they could be observed.

This is due to the risk of acute infusion related reactions these reactions which include fever chest pain hypotension hypertension dyspnea, Pruritus, Urticaria, angioedema and can include anaphylactic shock.

there can also be delayed type hypersensitivity so it’s important that the patient is aware of other things to look out for once they’ve left the hospital setting
for this reason patients must be in a position where appropriately trained medical staff can step in and administer drugs such as adrenaline antihistamines corticosteroids and provide artificial airway if the patient was to suffer any of these reactions
Therefore infusions that are given like this will be given in a in a hospital setting where there is access to these types of medications in case these infusion reactions were to occur the risk of the reaction is greatest during the first two infusions and away to help to prevent it is to give the patient a pretreatment of antihistamines hydrocortisone and all paracetamol as well to help to control any reaction if a patient has previously reacted to the medication but the medical team have decided that the medication should be continued to the reaction obviously wasn’t the anaphylactic type reaction then to reduce the risk for future infusions then the rate of the infusion would be lowered so it will take longer for that infusion to be given to a patient

The delayed hypersensitivity reactions are more likely with an increased duration of infliximab interval so as you saw on the dosing regime on the previous slide once the patient has been started they then undertake an their infusions every eight weeks if that interval is greater the patient is at Increased risk of delayed hypersensitivity patients are retreated after a long period without their infliximab then they should have really very close monitoring for delayed type hypersensitivity

as infliximab is a foreign protein antibodies to to the infliximab may develop and have been associated with an increased frequency of infusion reactions so two to three times greater risk of infusion reactions if patients do have antibodies to the infliximab and also a reduced duration of response to their treatment for this reason infliximab should always be used with another immunomodulator such as methotrexate as this reduces the risk of antibodies forming against the infliximab

in practise if patients do not have reactions and do not have these infusion reactions then it’s likely that after three or four infusions that the duration of administration so the two hours may be reduced down to potentially one hour but it mustn’t go below one hour

in line with what you’ve already heard about biologics and the potential side effects of them the very common side effects of infliximab include infection and particularly upper respiratory tract infection headache and infusion related reaction and pain most serious ones involve serious infections and reactivation of infections new or worsening heart failure delayed hypersensitivity haematological reactions, demyelination disorders hepatobiliary events Malignancy’s and serious infusion reactions

so when you think about the group of patients that these drugs will be cautioned and contraindicated in you can see the reasons for that cause the side effects of the drugs can cause would worsen those conditions if a patient was to have them

Question 19

Infliximab cautions/contraindications?

Answer 19

Contraindications so it will be contraindicated any patient has a hypersensitivity to other murine proteins who already has a severe infection tuberculosis abscesses or opportunistic infections moderate to severe heart failure and it’s also cautioned in patients at risk of infection patients with demyelinating disease malignancy mild heart failure and in the elderly if we just think for a second about how these drugs are eliminated from the body therapeutic monoclonal antibodies are predicted to be non specifically metabolised to peptides and amino acids that can either be reused in the body for de Novo synthesis of proteins or they can be excreted by the kidneys.

Patient advice patients should be informed to carry an alert card so that any healthcare professional would know that they were receiving monoclonal antibody that they should seek advice if they notice symptoms of tuberculosis or persistent cough weight loss fever also if they notice any symptoms of blood disorders such as fever sore throat bruising and bleeding and any delayed hypersensitivity this may involve things such as fever malaise pruritus urticaria and wheezing.

Question 20

Role of pharmacist in biologics administration?

Answer 20

The role of a general pharmacist in relation to biological agents as we’ve said this is a very specialised area of pharmacy won’t be something you come across very often and the important thing to be aware of is that you recognise these types of medicine and are able to apply your knowledge and the fact that some of the information you will need to be looking up such as the doses and the monitoring etc in which case you’re going to be looking at local guidance the summary of product characteristics for example and guidance in relation to the disease that they’re treating we need to be making sure as pharmacist that we have the correct indication so that the patient is receiving the drug for the correct indication that the correct dose based on a patient’s weight is being administered and that the correct frequency and duration of treatment is occurring if you think about that in terms of infliximab it’s important that we don’t have long periods where the patient doesn’t receive the infliximab as that would increase the risk of reactions for example and ensuring that appropriate monitoring is taking place with this continual checking that the drug is still appropriate for use in the patient