PHSC 574. Pharmacokinetics Assignments Near End-Semester Assignment The following extra assignments are required for the completion of this course. A grade maximum of 40 points will be assigned upon...

Biopharmaceutics


PHSC 574. Pharmacokinetics Assignments Near End-Semester Assignment The following extra assignments are required for the completion of this course. A grade maximum of 40 points will be assigned upon successful completion. You may NOT work in groups or ask other students for help in completion of this assignment in any way. You may use any textbook or any other reference book you would like. Any calculation, graph or other requirement can be accomplished with the aid of any spreadsheet program or other program available to you, such as Excel. You can paste Excel figures in this Word document and send it to me via e-mail or hard-copy. Problem 1. (10 points) A drug (100 mg) was administered by rapid IV injection into a 70-kg adult male. Blood samples were taken over a 7-hour period and analyzed for intact drug content. The results are shown in the Table. Assume that the drug is distributed via a two-compartment model. Using the Methods of Residuals, calculate the values for intercept A and B and slopes , , k10, k12, and k21. Make sure you label the graphs clearly and with the appropriate axis and units! Time (h) Cp (g/mL) 0 70.00 0.25 53.80 0.5 43.30 0.75 35.00 1 29.10 1.5 21.20 2 17.00 2.5 14.30 3 12.60 4 10.50 5 9.00 6 8.00 7 7.00 Composing semi-log graph with distribution slope  and elimination phase slope  (3 points). A = ____________ (0.5 point) B = ____________ (0.5 point)  = ____________ (0.5 point)  = ____________ (0.5 point) Write equation that describes the curve _____________________ (1 point) k10 = ___________ (1 point) k12 = ___________ (1 point) k21 = ___________ (1 point) What would be the steady-state concentration if you were infusing this drug at 40 mg/h? _____________ (1 point) Problem 2. (10 points) Intravenous bolus doses are repeated every six hours with the following information known about the drug: VD = 60 L, Dose = 1000 mg, k = 0.12 h−1, dosing interval equal to 6 hours. Calculate Cp vs t for a single dose from t = 0 until t = 60 hours. (Hint: calculate Cp at each hour). Use this data to create a Cp vs t profile to show the approach to steady state with this dosing schedule, repeating the bolus dose every six hours (use the method of superposition (see book) and a spreadsheet to handle this calculation). Plot the projected total Cp vs t data and turn in the plot. Compare and contrast the superposition principle results with those obtained by using the equations provided in the book or handouts and calculating individual concentrations at several times for the last interval plotted. Turn in: Cumulative Cp vs t plot (3 points) R = ____________ (1 point) Cmin∞ = ___________ (1 point) Cmax∞ = ___________ (1 point) Cav∞ = ___________ (2 points) Cp∞ when 8th dose missed = ___________ (2 points) Problem 3. (10 points) A drug is metabolized by a CYP3A4 enzyme. During several concentrations of the drug the following enzymatic rates of the CYP3A4 enzyme were obtained: [drug] v mg/L (mg/L/h) 0.001 0.004 0.002 0.007 0.004 0.013 0.008 0.023 0.016 0.036 0.032 0.049 0.064 0.061 0.128 0.069 0.256 0.074 0.512 0.077 Compose a Lineweaver-Burk plot to determine the maximal velocity (Vmax) and the Michaelis-Menten constant (KM) of the drug for the CYP3A4 enzyme. Composing graph with proper axes labelled (3 points) Vmax __________ (1 point) KM ___________ (1 point) Suppose a competitive inhibitor of the CYP3A4 enzyme is added simultaneously with the drug. The inhibitor has the following characteristics: concentration (0.05 mg/L), Ki = 0.025 mg/L. Calculate the velocity of the CYP3A4 enzyme in the presence of this inhibitor and the same drug concentrations. Plot the data together with the data obtained without the inhibitor in one graph. Composing drug versus velocity plot with and without the inhibitor (2.5 points) Suppose the same drug acted as a non- competitive inhibitor of the CYP3A4 enzyme. Calculate the velocities of the CYP3A4 enzyme in the presence of this inhibitor and the same drug concentrations. Plot the data together with the data obtained without the inhibitor in one graph. Composing drug versus velocity plot with and without the inhibitor (2.5 points) Problem 4. (10 points) Three doses of a new drug were administered via IV bolus injection to a group of patients and the average plasma concentrations of the drug versus time date were reported: Dose = 10 mg Dose = 200 mg Dose = 500 mg Time (h) Conc (mg/L) Time (h) Conc (mg/L) Time (h) Conc (mg/L) 0 0.5 0 10 0 25 2.75 0.3 5 7 16 12.5 4 0.25 14.5 2.5 26 6.25 11 0.0625 19 1.25 39 1.27 20 0.0125 25 0.48 44 0.46 33 0.08 48 0.22 Question a: Plot the three data sets on the same semi-log graph. (2 points) Question b: For each dose, identify the portion of the Cp versus t data which is linear. Use the linear portion to calculate the half-life for the 3 doses. (1 point) Question c. For each of the 3 doses, estimate the time required for the Cp to decline from Cp0 to 0.5 Cp0. Are the values different? Why? (1 point) Question d: Using the trapezoidal method, calculate the AUC0∞ of the drug for the 3 doses. (2 points) Question e: Plot the AUC0∞ versus the administered dose on a regular graph. Is the relationship linear? Why? (2 points) Question f: Calculate clearance for all 3 doses, Are the values dose-dependent? (1 point) Question g: Calculate the volume of distribution for the 3 doses. Are they similar? Why? (1 point) PHSC 574. Pharmacokinetics Assignments Mid-Semester Assignment The following extra assignments are required for the completion of this course. A grade maximum of 20 points will be assigned upon successful completion. You may NOT work in groups or ask other students for help in completion of this assignment in any way. You may use any textbook or any other reference book you would like. Any calculation, graph or other requirement can be accomplished with the aid of any spreadsheet program or other program available to you, such as Excel. You can paste Excel figures in this Word document and send it to me via e-mail or hard-copy. Problem 1. (10 points) The bioavailability of phenylpropanolamine hydrochloride was studied in 24 adult male subjects. The oral administration is 25 mg. Assume the drug follows a one-compartment model with first-order elimination kinetics. The following mean plasma concentrations are available: Time (h) Cp (ng/mL) 0 0 0.25 51.33 0.5 74.05 0.75 82.91 1 85.11 1.5 81.76 2 75.51 3 62.98 4 52.32 6 36.08 8 24.88 12 11.83 18 3.88 24 1.27 Calculate the rate constant of oral absorption (ka) and the elimination rate constant (k) by the Methods of Residuals (= methods of “feathering”). From your values calculate tmax. Composing semi-log graph with axes labeled (2 points) ka = 2.967 h-1 (3 points) k = 0.186 h-1 (2 points) tmax = 0.996 h (3 points) Problem 2. (10 points) The following infusion data was obtained from infusing theophylline at 90 mg/h for 36 hours (see Table below). Plot the data, label axes clearly. Calculate the half-life of elimination (t½) and the volume of distribution (VD) for this drug. If the patient weighed 80 kg, calculate the VD in terms of L/kg of body weight. What would be the steady state concentration if the infusion rate was changed to 50 mg/h? Time (h) Cp in g/mL 0.1 0.2 1 2.1 2 3.9 3 5.5 4 6.9 6 9.1 8 10.8 10 12.1 14 13.7 18 14.7 20 15.0 24 15.4 36 15.9 42 6.9 48 3.0 54 1.3 60 0.6 Composing graph with axes labels (2 points) VD = ___________ (2 points) t ½ = ___________ (2 points) VD in L/kg _______ (2 points) Steady state Cp if 50 mg/h ____________ (2 points)