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Pages:
18 pages/≈4950 words
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9 Sources
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Other
Subject:
Health, Medicine, Nursing
Type:
Coursework
Language:
English (U.K.)
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MS Word
Date:
Total cost:
$ 93.31
Topic:

Drug Discovery and Clinical Trials and Clinical Pharmacology

Coursework Instructions:

QUESTIONS

  1. You are considering developing a biosimilar of a monoclonal antibody therapy.

A)   Identify the challenges you may face during development (50%) and

B)   What would you need to do to ensure the efficacy and safety of this drug, compared with the development of a traditional generic drug (50%).

  1. You are developing a new drug JM/B-2022 which belongs to the class of drugs known as kinase inhibitors. During phase III clinical trials it is evident that the efficacy and plasma concentration of the new drug varies considerably when taken with other medications.

Discuss:

A)   The possible types of drug-drug interactions (40%)

B)     How the impact of these interactions could be monitored, the safety of the patient assured and the clinical impact of JM/B-2022 maintained (60%).

  1. You saw an article on the internet that said eating vanilla ice cream could increase your risk of paracetamol poisoning. You did a bit of research and found the following data sets with vanillin, extracted from vanilla using serum enzymes alkaline phosphatase (ALP), aspartate transaminase (AST) and alanine transaminase (ALT) as markers of liver damage (Tables 1 & 2).

A)   Discuss the mechanism(s) leading to hepatoxicity for paracetamol and carbon tetrachloride. (60%)

B)   How might exposure to vanillin, a sulfotransferase inhibitor, cause an increase in liver damage following a non-hepatotoxic dose of paracetamol or carbon tetrachloride? (40%)

  1. You are working for a capital investment company that is looking to make a multibillion-pound investment in developing a new medicine. You have been tasked to review information from the Peterson-KFF Health System Tracker data (see Table 3 below) to identify which disease the company should invest in to develop a new drug treatment.

Table 1: Distribution of age standardised rate of Disability Adjusted Life Years (DALYs) due to select conditions per 100,000 population (2019).

Choose a disease from the table you would like to treat and provide:

A)   A critical description of the factors you would take into account when identifying the condition you have chosen (30%).

B)   An overview and critique of the pre-clinical studies that would need to be conducted (30%),

C)   A suggestion of the clinical trials and data that would need to be collected to include discussion of the possible inclusion and exclusion criteria as well as measurable endpoints to assess efficacy (40%).

  1. You are reviewing a research paper investigating the impact of alcohol on paraquat toxicity in rats. Alcohol is administered either on its own (E), before paraquat (BP), mixed with the paraquat (MP) or after the paraquat exposure (AP). The paraquat alone group is PQ.

A)   Briefly discuss the mechanisms leading to the toxicity of

i)    alcohol (30%)

ii)   paraquat (30%).

B)   What does Figure 1 (below) suggest about the impact of alcohol consumption on paraquat plasma levels? (10%)

Figure 1: Serum paraquat (PQ) concentrations against time (hours) in each group. (A) PQ group; (B): BP group; (C): MP group and (D): AP group.

C)    In Table 1 (below) the relative lung toxicity (recorded as histopathological scores) from each group is shown. What is the impact of alcohol consumption on paraquat toxicity? C is a control group. (10%)

D)   The enzyme myeloperoxidase (MPO) catalyses reactions which increase levels of reactive oxygen species such as OH-. What does Figure 3(A) indicate about how alcohol might be affecting paraquat toxicity? (10%)

E)    What pharmacokinetic drug:drug interaction might be responsible for the affect of alcohol on paraquat toxicity? (10%)

  1. You are working on the reformulation of a nerve agent antidote containing atropine and pralidoxime and are using malathion and VX as test agents.

A)   Discuss the mechanisms behind malathion and VX nerve agent lethality and how the antidote reverses these effects. (60%)

B)   Using an appropriate animal model with skin exposure to malathion and VX, and intravenous administration of the antidote, what preclinical animal data would be important to obtain before moving to human clinical trials. (20%)

C)   What precautions would need to be taken when designing a human trial of the antidote. (20%)

Coursework Sample Content Preview:
QUESTION 1
A）
Muromonab-CD3 is an example of biosimilars of monoclonal antibody (mAbs)therapy that targets and destroys antigens. The biosimilar was first commercialized in 1986 for the treatment of transplant rejection in humans. In Europe, infliximab was the first biosimilar mAb to be authorized in September 2013 and the US Food and Drug Administration approved Zarxio TM, filgrastim, -sndz, Sandoz in March 2015. Biosimilars represent various biological medicinal products containing versions of active substances of already authorized original biological medicinal products or reference medicinal products within the European Economic Area (EEA). These products are similar to reference medicinal products in terms of biological activities, quality characteristics, efficacy, and safety, and have no clinically important differences from reference products in terms of safety and efficacy. To date, the United States has not approved any biosimilar mAb for clinical use due to several challenges associated with biological medical products. For this reason, it is necessary for relevant pharmaceutical companies and the academic community to understand both the costs and stages associated with the processing of biosimilar mAbs.
Compared to other biosimilars such as biological and small molecules, monoclonal antibodies represent complex challenges due to their high molecular weight and have more complex structures. Examples of small molecular drugs as aspirin is comprised of about 21 atoms and 180 Daltons, while a typical mAb, which is a complex biopharmaceutical, has 20,000 atoms of 150,000 Daltons. The structure of small molecular drugs is also well defined but mAbs have more complex structures that are challenging to define. mAbs are highly complex molecules consisting of secondary and tertiary structures that are also subject to post-translational modifications such as glycosylation. While the molecular characterization of mAbs can be extremely precise, reproducible, and reliable, challenges in heterogeneity also exist that make physicochemical characterization a challenge. Pharmaceutical companies can produce small molecules at relatively lower prices without the need for extensive clinical trials. The complexity of biosimilar mAb therapies also introduces batch-to-batch variations, even in the originator molecules. Furthermore, characterization techniques used to reveal similarities in folded tertiary and quaternary structures such as x-ray crystallography and nuclear magnetic resonance are yet to become robust for industrial application.
Similar to biological molecules, biosimilars of mAb therapy may only be derived from living organisms as opposed to small molecules that can be chemically synthesized in the laboratory. In terms of development cost and time to market, biosimilars take longer, 7-8 years, and have a budget of $100-300 million, compared to generic products that take 2-3 years with a budget of $2-3 million. Compared with biologics, biosimilars have a shorter time to market and lower development cost with biologics costing 800 million and time to market of 8-10 years，note that the cost of developing biosimilars is significantly higher compared to their generic equivalents because of the higher cost of manufacturing and...
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