BIOE 426/625   Pharmaceutical engineering

Spring 2004

Due Feb 12, 2004

Topics:   Pharmacokinetic modeling, urine analysis following I.V. bolus dosing with metabolism,  Oral dosing

 

1. A rapid IV dose of 200 mg is administered to an adult subject and the cumulative amount of drug excreted in the urine is determined as a function of time.  What is the overall apparent 1st order elimination rate constant?   What is the value for the rate constant by  renal and nonrenal excretion?

Time (hour)

Cumulative amount of drug excreted (mg)

2.0

22

4.0

42

8.0

72

12.0

94

16.0

110

20.0

121

24.0

129

48.0

150

T= infinite

150

 

 

 

 

2.  Given the data in Table 1 and 2, calculate ka, F (the bioavailablity), kel, and V. Assume a one compartment linear model.

Table 1. Plasma Concentrations Measured after a 100 mg I.V. Bolus Dose of Drug X to Subject Y

Time (hr)

Concentration (mg/L)

1

5.72

3

4.14

6

2.56

 

Table 2. Plasma Concentrations Measured after a 300 mg Oral Dose of Drug X to Subject Y

Time (hr)

Concentration (mg/L)

0.25

2.28

0.5

4.33

0.75

5.67

1

6.89

1.5

8.81

2

9.31

3

9.68

4

10.25

6

7.51

9

4.98

12

3.25

 

 

 

 

 

3.           The blood concentration time profiles following oral administration can often be described by  the biexponential equation

 

C = Ci e-Sz*t -  Ci e-Sl*t

Where Sz and Si are the negative slopes of the 1st order plots for the terminal (Sz) and feathered (Sl) data.    When a 70 kg  person was given a 500 mg oral dose, the drug exhibited linear pharmacokinetics with Sz =0.087 hr-1 and Sl =0.72 hr-1and Ci= 23 mcg/ml.

            When a 250 mg dose was given by rapid I.V. injection to the same subject 

            C = 16.7 mcg/ml  exp(-0.087 hr-1 * t).

 

What is the bioavailable dose?  What dose Sz represent

 

 

4.     In a clinical study (diSanto and DeSandte, JPS 64:100,1975) prednisone was administered to 22 adult healthy volunteers (average weight 64.5 Kg) either as  one 50 mg tablet (product A) or ten 5 mg tablets (product B).  The following data was observed:

 

Time  (hr)        Concentration (mcg/100ml plasma)

                                    Product A        Product B

0.5                   40.8                 57.3

1                      70.0                 77.1

2                      79.5                 82.3

3                      80.7                 69.4

4                      68.6                 60.6

6                      49.4                 60.6

8                      35.0                 33.7

12                    15.3                 17.4

24                    2.1                   3.0

 

Calculate peak time (tmax) and Cp max and AUC0-infinity for each product

Discuss and compare the rate and extent of absorption of each product.  Are they bioequivalent (within 5%)?

 

 

 

 

5.     When marijuana is smoked, peak blood levels of the parent drug , Delta-9-Tetrahydrocannabinol (THC) are achieved almost immediately.  Because it delivered to the lungs, there is virtually no 1st pass liver metabolism, it can be modeled like an IV administration (although the bioavailability is low and varied due to inhalation techniques).   Some THC is excreted unchanged but it is also metabolized into a major metabolite (11-Hydroxy-THC) which is an active metabolite along with several other minor metabolites.  It is possible to model the pharmacokinetics as having partial parent drug excretion along with 2 metabolites: a major 11-H-THC  and  a minor 9-carboxy-THC (THC-COOH) . Assume that a 1-comparmental model will represent your data and that both metabolites are produced via phase I reactions, e.g. hydrolysis or oxidation, of the parent THC.

 

a. Draw the schematic (black box diagram) that would describe the pharmacokinetics of THC using the above model. 

b. Write the differential equations describing the system (rate of change of parent drug and each metabolite)

c. Integrate the DE that will describe the amount of the principal metabolite (11-Hydroxy-THC) in the urine at any time.

d.     A friend of a friend asks you to figure out if he will pass a drug test for his new job.  He will be having his physical in 30 days and smoked pot last night (bioavailable dose of 5 mg).  You assume that the test will be for the metabolite, 11-hydroxy-THC, and assume that it has a metabolism rate constant and elimination rate constant of 0.001 day‑1 and 1x10-6 day -1 respectively.  Also assume the metabolism rate constant for THC-COOH is 5x10-4 day-1  and the elimination rate constant of the parent drug THC is 0.001 day –1.  The analytical test can detect 1 mg in a urine sample.   Here is a link if you want to know more about THC pharmacokinetics (it is not needed for the problem)  http://www.dft.gov.uk/stellent/groups/dft_rdsafety/documents/page/dft_rdsafety_504567-05.hcsp. 

Disclaimer:  The rate constants are fictional and are for educational purposes only.  Do not attempt to use these in a real life situation.

 

 

 

6.   Read the Taxol oral bioavailability paper by Sparreboom et al. Write a summary ( < 1 page) of their study.   You should be able to give an overview of their work (purpose, experiential procedure, findings)  and point out the strengths and weaknesses of their research.   Don’t just rewrite the abstract.