PHAY0021 THE PROCESS OF DRUG DEVELOPMENT 2023Java

Java Python PHAY0021

THE PROCESS OF DRUG DEVELOPMENT (TPODD 2)

May 2023

1. Answer ALL parts of the question

Asthma medications are usually administered via inhalation. Your company has developed both an inhaler and a tablet containing the same active compound X. The company would like to release the tablet on the market, so you are asked to compare the effect of the tablet with that after inhalation.

It was determined that the area under curve (AUC) of 1 mg of X administered via inhalation is 20 mg h/L. The AUC of a 5 mg X tablet is 60 mg h/L.

a) How does the bioavailability of inhalation compare to the tablet?             (5% of marks)

b) Explain which parameters affect the bioavailability of the tablet.            (10% of marks)

You are asked to design a preclinical animal study to evaluate possible oral administration of a higher dose of compound X.

c) Describe which study you would perform. Your answer should include a discussion of the possible practical issues related to the selected route of administration.          (55% of marks)

Following a sub-chronic repeated dose study, you are asked to evaluate the weights of liver, spleen and kidneys after the post mortem analysis of the rats.

d) From the available data, identify the no-observed-adverse-effect level (NOAEL). Justify your answer.   (10% of marks)

e) Considering all the data available so far, which route of administration would you propose to use and why?   (20% of marks)

2. Answer ALL parts of the question

Tacrolimus is an immunosuppressant drug that is used in combination with other medicines to prevent rejection following a kidney, heart, liver, or lung transplant, with blood concentrations over 15 mg/ml found to be toxic. Tacrolimus is predominantly metabolized by CYP3A4 and CYP3A5.

a) Briefly explain the overall function of CYP proteins and name two major isoforms of this pro PHAY0021 THE PROCESS OF DRUG DEVELOPMENT 2023Java tein family.  (15% of marks)

b) Please explain possible risks of co-administering tacrolimus with other drugs, or ingesting grapefruit juice after tacrolimus administration. You may use a drawing to support your explanation.   (25% of marks)

c) Describe two modifications to the tacrolimus structure that can occur during metabolism. Using the heavy atom numbering in the tacrolimus structure shown above, provide three specific sites where these reactions could take place.   (40% of marks)

d) Please briefly explain an assay to evaluate if a compound can act as an inhibitor of one of the main CYP isoforms and provide reasonable classification bands for potent, moderate and weak inhibition.   (20% of marks)

3. Answer ALL parts of the question

a) Explain which physicochemical parameters of molecules are important to determine their developability and enhance the probability of success during the clinical trials.   (25% of marks)

b) Why is the aqueous solubility of a new candidate molecule important?   (25% of marks)

c) How can you measure the solubility of a compound and how does it relate to its chemical structure, lipophilicity, pKa and absorption?    (15% of marks)

d) Discuss how chemical modification can be considered to increase the aqueous solubility of a drug discovery compound during lead optimisation.   (35% of marks)

4. Answer BOTH parts of the question

In recent months several pharma companies have withdrawn drugs that were originally approved by accelerated approval pathways. For example, GSK recently withdrew Blenrep, which had received FDA accelerated approval in 2020, because it was proven to be ineffective as a monotherapy in confirmatory trials.

a) Discuss the regulatory initiatives in place for drugs to receive accelerated approval and explain why such late withdrawals after approval can occur.   (50% of marks)

b) Outline the current strategies being adopted to reduce failure and improve the development of new cancer drugs and how precision medicine clinical trial design can help