PHAY0021 THE PROCESS OF DRUG DEVELOPMENT 2019Prolog

Java Python PHAY0021

THE PROCESS OF DRUG DEVELOPMENT (TPODD 2)

May 2019

1.       Answer ALL parts of the question

A new drug, currently at the preclinical stage of development, has a proposed therapeutic indication for a disease that affects many elderly patients. Since in vitro studies highlighted a possible concern that the drug may   cause hepatotoxicity, preliminary acute dose studies were carried out in both young and older rats at a range of dose levels. The dose response curves obtained are shown below. The major toxicological finding in both groups was hepatic necrosis.

a)       Describe the mechanism and characteristics of hepatic necrosis.  (30 % of marks)

b)        Discuss the dose response curves below; including in your answer the main

reasons why on-target toxic effects occur and why it is important to know about these.                (40 % of marks)

c)        The research team is designing the future reproductive toxicity studies that may need to be carried out before clinical trials. What considerations should be taken into account?                                (30 % of marks)

2.       Answer ALL parts of the question

a)       Why is lipophilicity one of the most important physicochemical properties that should be optimized in early drug discovery?      (25 % of marks)

b)   PHAY0021 THE PROCESS OF DRUG DEVELOPMENT 2019Prolog ;      Define lipophilicity and describe how it can be measured?          (25 % of marks)

c)        How does lipophilicity relate to solubility and permeability?          (25 % of marks)

d)        How does the ionization of the compound influence lipophilicity and in vivo biodistribution?     (25 % of marks)

3.       Answer ALL parts of the question

a)       A  significant number of drugs have been withdrawn from the market post approval. Usually this is due to serious adverse effects that were not identified during development of the drug. Compare the evidence that is known to the regulatory body at the time of a new drug authorization with the information that is not known and how this can lead to drug failure post approval.   (40 % of marks)

b)       A  key challenge for regulators and stakeholders is to provide earlier patient access to innovative medicines. Discuss the regulatory initiatives in place to improve patient access to drugs before they are licensed.          (40 % of marks)

c)        How can drug repurposing improve patient access to drugs?      (20 % of marks)

4.       Answer BOTH parts of the question.

a)       Describe and explain the molecular mechanisms involved in Phase I metabolism of drugs by CYP450 enzymes.        (50 % of marks)

b)       Explain the term prodrug and why the development of a prodrug may be advantageous in drug discovery. Use THREE (3) examples of prodrugs that illustrate the different advantages you identify