MMED3934 Principles of Pharmacology And Toxicology Assignment – Australia.

Comparison of oral versus intravenous formulations and routes of drug administration
Pilozolam is a fictional medicine that is available in both oral and intravenous (IV) formations. A phase 1 clinical trial determined the following pharma cokinetic properties for pilozolam in a healthy volunteer cohort.
i. Bio availability: 70%
ii. Elimination half-life: 12 hours
Question: 1
Describe the key similarities and differences in the theoretical plasma concentration time profiles for pilozolam exposure following a single oral dose of pilozolam versus a single intravenous dose of this drug.
MMED3934 Principles of Pharmacology And Toxicology Assignment – Australia.

MMED3934 Principles of Pharmacology And Toxicology Assignment - Australia.

Question: 2
Clinical implications of oral versus intravenous dosing
Discuss the clinical implications (in terms of dose and time course of action) of any differences in the pilozolam plasma concentration time profiles following oral versus intravenous administration of this drug.

Calculating volume of distribution
Aplenzole is a fictional drug that has the following phamacokinetic parameters:
i. Hepatic clearance (CL H ): 40L/hr
ii. Renal Clearance (CL R ): 10L/hr
iii. half life (t 1/2 ): 5hr
Calculate the volume of distribution (V D ) for this drug (Provide your answer in liters (L) as a whole number) ANS: 361 L

Interpretation of changes in drug distribution
A drug interaction results in the displacement of aplenzole from plasma proteins.This results in a doubling of the volume of distribution for this drug.

Question: 6
Making reference to any equations and parameters that relate these concepts describe the impact of increasing volume of distribution on the length of time aplenzole will stay in the body.

Mechanisms of drug clearance
Zarorolac is a fictional orally administered targeted oncology medicine that is being developed as a treatment for liver cancer. During a phase I multiple ascending dose trial involving healthy volunteers these phama cokinetic parameters were determined following oral administration of the drug:

i. Systemic Clearance: 85L/hr
ii. Fraction Unbound in Blood: 0.25
iii. Fraction Excreted unchanged in Urine: 0.05
A second phase I drug interaction study is now being planned where zarorolac will be co-administered with a strong inhibitor of the primary enzyme involved in zarorolac metabolism.

Question: 7
Based on the parameters described above, predict the impact of co-administering the strong inhibitor on the following pharma cokinetic parameters for zarorolac:

Translation from healthy volunteers to oncology patients
Once zarorolac has completed the phase I clinical trials in healthy volunteers it will move into a phase II clinical trial in cohort of liver cancer patients to assess the drugs safety and toler ability. Compared to the healthy volunteers these patients will on average have reduced blood flow to their liver and kidneys and will have less functional liver tissue.

Question: 8
Based on your understanding of these patient factors describe the likely changes in zarorolac bio availability and half life that will be observed in the liver cancer patients and comment on how these changes will affect the oral dose that should be given to the cancer patients to achieve a comparable exposure profile to that observed in the healthy volunteers.

Determining intravenous infusion rate
You are looking after a post operative patient that a surgeon has suggested should receive an infusion of a fictional analgesic called morphipalene. In making your decision about how to manage the patient you consult a general drug information resource that contains the following phama cokinetic information regarding the drug:
i. Bio availability (F): 50 %
ii. Urinary excretion (f e ): 0.08
iii. Fraction unbound in plasma (f u ): 0.16
iv. Systemic Clearance (CL s ): 60 L/hr
v. Volume of Distribution (V D ): 320 L
vi. Half life (t 1/2 ): 3.7 hrs

Question: 9
Based on this information, calculate the intravenous infusion rate (in μg/hr) that will be required to maintain a steady-state blood concentration of 15 μg/L:

Management of a dosing error
When working out the infusion rate for morphipalene you were distracted and accidentally calculated a dose that resulted in a blood concentration eight times higher than the steady state concentration you were aiming for. You immediately stop the infusion but now need to work out how long it should be before you start administering the drug again.

Question: 10
Referring to any relevant pharmacokinetic principles, justify how long you will wait (in hours) before it will be safe for you restart the patients infusion (at the correct dose).

Systemic Clearance Extended Calculation
A pharmaceutical company is developing a new drug called trilitacept. They have just determined the following pharmacokinetic parameters from a Phase I human study:
1. Fraction unbound (f u ): 0.5
2. Clearance by active secretion (CL sec ): 2L/hr
3. Fraction reabsorbed (FR): 0.25
4. Hepatic Extraction Ratio (E H ): 0.15

Question: 11
Showing all working out and stating all assumptions Calculate the total SYSTEMIC CLEARANCE for trilit acept.

Question: 12
Variability in drug exposure
Identify one PATIENT FACTOR that may alter trilitacept clearance and specify the pathway involved in trilit acept clearance that will be affected by the patient factor you have selected.

Variability in drug exposure
As a fictional new cardiovascular medicine fleximuran enters Phase III clinical trials it is determined that the drug requires hepatic activation in order to elicit a therapeutic effect. Further studies identify that the sole enzyme involved in the activation of this drug is CYP2C19.

Question: 13
a) Select ONE specific factor (from the categories environmental, genetic or physiological) that may contribute to variability in the activation of fleximuran and explain the potential consequences of this variability in terms of treatment response and toler ability.

Question: 14
Addressing variability in drug exposure
Briefly discuss how variability in fleximuran activation may be addressed in clinical practice. Your response should include consideration of both the intention of the approach and the way that the approach could be implemented.

MMED3934 Principles of Pharmacology And Toxicology Assignment – Australia.

MMED3934 Principles of Pharmacology And Toxicology Assignment - Australia.

Adverse drug reactions
Sam a 63 year old male, has been treated with extended release lithium carbonate for the management of bipolar depression for the past 28 years. He has presented to the Emergency Department after experiencing increasingly frequent and severe episodes of dizziness and tremors over the past three days. On presentation, he is found to have a blood pressure of 86/43, and an irregular heart rate of approximately 41 bpm.

A panel of blood tests are ordered as part of Sam’s initial diagnosis and work up the results of which are all normal except for an estimated glomerular filtration rate (eGFR) of 20mL/min. The treating physician concludes that Sam’s symptoms are most likely the result of an adverse drug reaction resulting from his use of lithium carbonate.

Question: 15
Discuss the factors that are likely to have contributed to Sam’s presentation. (Hint: consider the consequences of long-term lithium use and the mechanism of lithium clearance)

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