PHA 4120 Second Exam Key Fall On my honor, I have neither given nor received unauthorized aid in doing this assignment.

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1 PHA 4120 Second Exam Key Fall 1997 On my honor, I have neither given nor received unauthorized aid in doing this assignment. Name Question Points 1. /10 ponts 2. /20 points 3. /10 points 4. /10 points 5. /10 points 6. /10 points 7. /20 points 8. /10 points TOTAL /100 points

2 1. (10 points) Two patients A and B receive an antifungal drug via constant rate infusion. The infusion rate was the same in both patients. The following plasma concentration time profiles were obtained A B a) A and B differ in one primary pharmacokinetic parameter. Discuss the above concentration time profile. Steady state levels are equal. For constant rate infusion: Cpss = k 0 /Cl. Thus, Cl is the same for both patients. Since the curves are not superimposed, it may be concluded that V d is different. K e is also different which explains the change in the terminal slope. b) Why is steady state reached faster in patient A? Roughly 5 half-lives are required to reach steady state. ln 2 t 1 / 2 = k e k e must be larger fr patinet A (faster elimination after stopping the infusion). Then, the t 1/2 is shorter and steady-state levels are reached faster. 1

3 2.) (20 points) T F When multiple drug doses are given and steady state is reached, the amount of drug eliminated during one dosing interval (τ) is equal to the drug dose T F A drug with a long half-life takes a shorter time to reach steady state than a drug with longer half-life. T F When developing a multiple dose regimen, doubling both the dosing interval and the dose will result in the same average plasma concentration. T F An increase in drug dose will result in higher plasma concentrations at steady state but will not change the time to reach steady state. T F If the dosing interval is decreased, the time to reach steady state is reduced. Dependent on t 1/2 T F Loading doses are administered prior to beginning a continuous intravenous infusion to provide an immediate as well as a sustained effect of the drug. T F For rapidly absorbed as well as slowly absorbed drugs, the bioavailable dose is directly related to the AUC. T F The faster the absorption rate of a drug the steeper the terminal slope of the downhill portion of the concentration time profile. K e independent of ka must assume normal kinetics (albeit this is obvious from the wording of the statement) T F Assume a drug which is mainly eliminated through hepatic metabolism. The area under the concentration time profile after oral administration of such a drug is affected by the hepatic extraction ratio E T F For a two-compartment body model drug, the volume of distribution of the central compartment is larger than the volume of distribution at steady state. V d centreal is smaller prior to distribution. This results in higher, short-lived concentrations just after injection. 2

4 3.) (10 points) A drug is given as an oral sustained release product. A pharmacist attempts to derive the half-life of a drug from the terminal phase of the concentration (time profile). Discuss. The slope of the terminal phase will give k e only if k a >>k e, i.e. normal kinetics. If it is known that this drug follows normal kinetics, k e may be determined. Otherwise, there is no way to distinguish this from k a unless i.v. bolus dta is also available. For flip-flop kinetics (k a << k e ), the terminal slope represents k a and k e must be determined by feathering. 4.) (10 points) Describe in your own words, as briefly as possible, the general strategy applied in the dosing of a narrow therapeutic window drug using drug monitoring approaches. A dosing regimen is begun (dose, τ) based on general pharmacokinetic parameters for the patient (given sex, weight, body type, etc.). after the first dose, if two plasma samples are drawn at different time points, the k e may be determined for this patient. Assuming normal kinetics if oral dosing. If the dose is given by i.v. bolus, V d is also easily determined; Cl = k e V d. Having determine dthe actual Cl and V d enables us to customize the dosing regimen (D, τ) for this patient. 5.) (10 points) Mark the correct statement(s). If plasma concentrations are determined soon after an intravenous dose is given for a drug that exhibits biexponential elimination and if a one-compartment model (monoexpoential ) is assumed, the resulting elimination halflife: Cannot be determined Might be erroneous Will underestimate the terminal phase (t 1/2 too short) Will overestimated the half-life of the terminal phase ( t 1/2 too long) this will give erroneus answers, the error being determined by how different α is from β 3

5 6.) (10 points) The following equation describes the plasma concentration-time profile after multiple dosing of an i.v. bolus injection Cp = D Vd e ke t 1 1 e ke *τ D V d k e t = This equation can be sub-divided into three functional units. Each of these units is responsible for a certain pharmacokinetic property of the multiple dosing system. List the meaning (function) of each of the three group-terms the peak for the 1 st dose e = the elimination during the dosing interval Cp(peak): t=0, Cp(min): t = τ 1 = (1 k e the accumulation factor which tells us how much higher the concentrations t e ) steady-state compared to the 1 st dose. 4

6 7.) (20 points) A 60-year old female patient BA (70 kg) is being treated for a hospitalacquired, methicillin-resistant bacteremia. She was given a 1000 mg vancomycin loading dose and is now receiving 500 mg (infused over one hour) every 12 hours. The estimated elimination rate constant for vancomycin (population average) has been calculated to be hr -1. Her volume of distribution is 0.9L/kg (63L). Predict the steady state trough concentration C trough (just before starting the next infusion) for this dosing regimen. D = 500 mg, τ = 12 hr T = 1 hr K e = hr l V d = 70kg = 63L kg Cp ss( trough) Cp ss(trough) = = Cp Cp ( peak) e k ( τ T ) e D Cl T (1 e ket ss( peak ) = keτ ) = (26.6mg / L) e (1 e ) ; Cl = k e V 500mg [1 e (0.029hr x63l) (1hr) [1 e (0.029hr 1 d (0.029hr 1 1 x(12hr 1 hr) = 19.3 mg/l (0.029hr 1 x1hr) ] x12hr) b) What dosing interval (τ) would you recommend to attain a C peak (real peak directly at the end of infusion) of 25 mg/l and a C trough (real trough at the beginning of the next infusion) of 7 mg/l (ke= hr -1 ) ] Want: Cpss(max) = 25 mg/l Cpss(min) = 7 mg/l From equation sheet, Cp(max) ln Cp (min) τ = + T ke Assume that the infusion time is unchanged: T=1hr 5

7 Thus, 25 ln( ) τ = 7 1hr hr + = 44 hr + 1 hr = 45 hr this may be approximated as τ = 48 hr. 6

8 8.) (10 points) The following are plasma concentration time profiles for multiple i.v. bolus injections of drug X in two patients with identical pharmacokinetic properties for drug X. Discuss the figure shown below. Cp (ng/ml) Time (h) Initial concentrations are 40 ng/ml and 20 ng/ml. Cp0 = D/V d. If V d is the same, we conclude that the dose is doubled for one patient (thin line). From the graph it is also obvious that the dosing interval τ is doubled as well. Doubling both D and τ increases fluctuation seen in multiple dosing regimens. However, the average steady-state levels, Cpss, are identical for both patients above. 7