PHAR 5332

Key to Problem Set 7

Pankajini Mallick

pmallick@uh.edu

11/11/2015

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Question 1: Comment on the accuracy of the following statements with regard to drugs given as an oral multiple-dose regimen of fixed dose and fixed dosing interval.

a) Accumulation always occurs. (True) . The process of accumulation always occurs on multiple dosing, as some drug always remains in the body from the first dose when the second and subsequent doses are given.

b) The extent of accumulation increases when drug is given less frequently. (False).

The less frequently a drug is given, the lower its extent of accumulation.

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Question 1: Comment on the accuracy of the following statements with regard to drugs given as an oral multiple-dose regimen of fixed dose and fixed dosing interval.

c) The time to reach plateau following multiple-dose regimen depends on the frequency of drug administration. False.

The time to reach plateau depends on the elimination half-life.

d) At plateau, the amount of drug lost within a dosing interval equals the oral maintenance dose. Only true if F = 1. At steady state, the amount of drug lost in each interval equals the amount gained, that is the dose multiplied by the bioavailability. e) Larger volume of distribution, lower is the average plateau concentration. False. Css, avg is independent of volume of distribution.

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Question 2: The Principle of superposition in designing multiple dosing regimen assumes that:

a) Each dose effects the next subsequent dose, causing nonlinear elimination (FALSE). Each dose is considered as an independent event

b) Each dose of the drug is eliminated by zero-order elimination (FALSE). Infact drug is eliminated by first-order kinetics

c) Steady-state plasma drug concentration are reached at approximately 10 half-lives (FALSE). tcss = 4-5 t1/2

d) Early doses of drug do not affect subsequent doses (TRUE) e) The fraction of drug absorbed is equal to the fraction of

drug eliminated (FALSE). It is important to note that the drug is not at steady state, but only at steady state concentrations 4

Question 3: Indicate true or false

a) The Css ave, Css max, Css min to be achieved with 250mg q6h (every 6h) will be same as those of 500mg q12h of the same drug (True). As D/tau remains same

b) The tmax,ss after a multiple dosing of IV bolus is shorter than tmax,ss of single dose of the same drug (True).

c) The accumulation factor of a drug resulting from multiple dosing regime at steady state is determined by two parameters, k and dosing interval (τ) (True). MDFss is the maximal MDF and is therefore not affected by “n”

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Book Question 2

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Patient C.S. is 35-yr old female weighing 60 kg, and is to be given multiple IV bolus injection of an antibiotic. The effective concentration is 15 mg/ml. After the patient is given a single IV dose, the t1/2 and V are determined to be 3 hr and 196 ml/kg. a. Determine the multiple IV regimen for C.S. b. After the condition of CS is stabilized, CS will continue on therapy

with an oral tablet with F = 0.9. What will be the oral regimen? c. If the oral tablets are available in 125, 250 and 500 mg. How will the

dose for CS be prescribed? d. If your regimen requires tablets of different strengths, it needs to be

modified because CS has difficulty in distinguishing the products of different strengths.

e. Verify your oral regimen.

Book Question 2

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Provided: t1/2=3hr; k = 0.693/3 = 0.231 hr-1

V = 196 ml/kg * 60 kg = 11.76 L a. Determine the multiple IV regimen for C.S. Css ave = F.D/CL. = 15 mg/L Therefore, D/ = 15 * 0.231 * 11.76 / (1) = 40.75 mg/hr A reasonable will be 8 hr, so D = 40.75 * 8 = 325.98 mg b. After the condition of CS is stabilized, CS will continue on therapy with an oral

tablet with F = 0.9. What will be the oral regimen? Aiming at the same Css ave of 15 mg/L, Css=FD/CL* 15 = (0.9) * D / (0.231 * 11.76 * 8) = 362 mg

Book Question 2

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Provided: t1/2=3hr; k = 0.693/3 = 0.231 hr-1

V = 196 ml/kg * 60 kg = 11.76 L c. If the oral tablets are available in 125, 250 and 500 mg. How will the

dose for CS be prescribed? We can give 1 X 250 mg + 1 X 125 mg tablets (total = 375 mg) Verify: Css ave = (0.9 * 375)/(0.231 * 11.76 * 8) = 15.6 mg/L Acceptable regimen! d. If that is the case, then simply give 3 X 125 mg tablets which totals to

375mg. e. Same as verification in part c. Verify: Css ave = (0.9 * 375)/(0.231 * 11.76 * 8) = 15.6 mg/L Acceptable regimen!

Book Question 3

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What pharmacokinetic parameter is most important in determining the time at which the steady state plasma drug level (C av) is reached?

Ans: t1/2 determines the time to reach steady state. 4-5 t1/2 is required to reach steady state.

Name two ways in which fluctuation of plasma conc. (between Cmax and Cmin ) can be minimized for a person on a multiple dose regimen without altering Cav

• Reduce dose

• Reduce dosing interval

Book Question 4

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Book Question 11

The body clearance of sumatriptan (Imitrex) is 250 mL/min. The drug is about 14% bioavailable. What would be the average plasma drug concentration after 5 doses of 100 mg PO every 8 hours in a patient?(Assume steady state was reached.) Provided: CL= 15L/hr; F = 0.14 = 8h; D= 100mg Css ave = F.D/CL. = 0.933 mg/L

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Question 12

Cefotaxime has a Vd of 0.17L/kg and elimination half life of 1.5 hr. What is the peak plasma drug conc. in a patient weighing 75 kg after receiving 1 g IV of the drug 3 times daily for 3 days.

Vd= 0.17* 75 = 12.75 L

k = 0.693/1.5=0.462 hr-1

= 8 hr

Cssmax = Dose /Vd(1-e-k)

= 1000/12.75 (1-e-0.462*8)

= 76.47mg/L

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THANK YOU

QUESTIONS???

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