_basic pharmacokinetics - chapter 7: oral dosing

Basic Pharmacokinetics REV. 99.4.25 7-1Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/

CHAPTER 7 Oral Dosing

Author: Michael Makoid and John CobbyReviewer: Phillip Vuchetich

OBJECTIVES

After successfully completing this chapter, the student shall be able to

1. Given patient drug concentration and/or amount vs. Time profiles, the student will calculate (III) the relevant pharmacokinetic parameters ( , K, , , , ,

Clearance, MRT, MAT) available from oral data.

2. Given patient drug concentration and/or amount vs. Time profiles, the student will calculate (III) the K from the terminal portion of the curve.

3. Given patient drug concentration and/or amount vs. Time profiles, the student will calculate (III) the from either the curve stripping Moment techniques.

4. Given patient drug concentration and/or amount vs. Time profiles, the student will calculate (III) the Absolute Bioavailability from comparing IV and oral (or some other process which involves absorption) data.

5. Given patient drug concentration and/or amount vs. Time profiles, the student will calculate (III) the Comparative Bioavailability from comparing the generic to the inovator product.

6. Given patient drug concentration and/or amount vs. Time profiles, the student will qualitatively evaluate (IV) bioequivalence as determined by rate of absorption (peak time) and extent of absorption (Area Under the Curve - AUC, and ).

7. Given patient drug concentration and/or amount vs. Time profiles, the student will evaluate (IV) bioequivalence data.

8. Given patient drug concentration and/or amount vs. Time profiles, the student will lucidly discuss (IV) bioequivalence and recommend (V) to another competant professional if s/he believes products to be equivalent.

Vd km kr ka AUC

ka

Cp( )max

Oral Dosing


9. The student shall be able to properly use vocabulary relative to bioequivalence.

Oral Dosing


7.1 Oral dosing

7.1.1 VALID EQUATIONS: ( ORAL DOSING, PLASMA)

(EQ 5-18)

(EQ 5-19)

(EQ 5-20)

(EQ 5-21)

(EQ 5-22)

where = the comparative bioavailability

= the absolute bioavailabilty; the fraction of dose which ultimately reaches sys-temic circulation (which is made up of the fraction of the dose which is absorbedtimes the fraction which gets past the liver (first pass effect))

= absorption rate constant.

7.1.2 UTILIZATION

CpfDVd

------ka

ka K–--------------- e

Kt–e

kat––( )⋅ ⋅=

f AUC oral( ) Dose oral( )⁄AUC iv( ) Dose iv( )⁄

--------------------------------------------------------------=

CB AUC generic( ) Dose generic( )⁄AUC inovator( ) Dose inovator( )⁄--------------------------------------------------------------------------------------=

tp

ka K⁄( )ln

ka K–( )-----------------------=

Xa

v------ K AUC∞ Cp K AUC t⋅+( )–⋅=

CB

f

ka

Oral Dosing


Ampicillin (Problem 5 - 17)

The following information is available for ampicillin: 90% is excreted unchanged and a 250 mg IV bolus dose yields anAUC of 11 mic/mL*hr. The following blood level profile has been reported for two brands of ampicillin which weregiven as 500 mg oral capsules.

Find the following:.

a. k for both products.

b. for both products.

c. for both products.

d. AUC for both products.

e. for both products.

f. for both products.

g.

h.

i for a 250 mg IV dose.

j.

k. Are these two products bioequivalent? Why or why not?

l. What infusion rate would be necessary to maintain a serum

TABLE 4-7

Time (hr)MEAN SERUM LEVEL

LEDERLE BRISTOL

0.5 0.37 0.38

1.0 1.97 1.91

1.5 2.83 2.49

2.0 3.15 3.11

3.0 2.73 2.79

4.0 1.86 1.95

6.0 0.43 0.49

µgmL--------

ka

ku

f

tmax

Cl

Vd

Cp0

Cpmax

Oral Dosing


plasma concentration of 2mcg/mL

The data was plotted as above with the best fit line drawn. From the graph the fol-lowing parameters were derived:

2) In a clinical study (DiSanto & DeSante, JPS 64:100,1975) prednisone wasadministered to 22 adult healthy volunteres (average weight 64.5 kg) either as one50 mg tablet (product A) or as ten 5 mg tablets (product B). The following datawas observed:

Time (hours) Concentration (mic/100ml plasma)

A B

TABLE 4-8 Comparison of Ampicillin

Lederle Bristol Ratio (L/B)

0.688 0.635

0.858 0.831

1.74 1.8 0.97

3 2.9 1.03

AUC (trapaziodal) 11.4 11.6 0.98

K hr1–( )

Ka hr1–( )

Tmax hr( )

Cp( )max

µg mL⁄( )

Oral Dosing


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 48.0

8 35.0 33.7

12 15.3 17.4

24 2.1 3.0

Find ka's for both products.

Calculate peak time and Cp max and AUC for both products.

Can you conclude that these products are bioequivalent ?

(Reasons should include discussion of rate and extent of absorption)

Answer:

Oral Dosing


Product A Product B Ratio (A/B)

Ka (hr^-1) 1.19 1.8

Tmax (hr) 2 1.52 1.31

Cmax (mcg/100mL)83.2 82.8 1.00

AUC (trapazoidal)676.52 688.81 0.976

Can you conclude that these products are bioequivalent ?

No, Time to peak (Tmax) is outside guidelines.

3) Wilkenstein et al.(Gastroenterology 74:360,1978) tested 12 normal healthyvolunteers in a four way crossover design of four dosage forms containing 300 mgof cimetadine. The following data was obtained:

Oral Dosing


A B C D

A.U.C. (mic/ml x hr)------ 5.2 5.4

% recovered in urine intact77.177.147.149.0

Peak serum conc.(mic/ml)------ 1.53 1.44

Onset (hr) 0 0.34 0.65

Duration (hr) 4.5 4.0 4.2 4.4

Time to peak (hr)0 1.0 2.0

A = IV bolus B = IM inj. C = Oral Liq. D = Oral Tab.

The plasma concentration - time profile for product A is as follows:

time(hrs) (ug/ml) time(hrs) (ug/ml)

1 1.79 6 0.45

2 1.36 12 0.08

4 0.78

a} Using linear regression, find K & Cp0.

b} What is the absolute bioavailability (f) of the liquid.

c} How does that correlate with % recovered intact in the urine?

d} Would you consider the oral forms bioequivalent?

Why/Why not?

Oral Dosing


f} What infusion rate would you suggest to maintain a plasma concentration of0.75 mic/ml ?

g} How long would it take that infusion rate to attain a therapeutic plasma con-centration of 0.5 mic/ml ?

Answer:

IV Bolus Parameters:

Cp max2.4 mic/mL

AUC 8.5

K 0.283 hr^-1

Oral Dosing


a} Using linear regression, find K & Cp0. (graph)


5/2/8.5 = 0.61


Very well. Only 61% (f) of liquid gets in and you would expect only 77% of that toshow up in the urine because only 77% of the IV dose shows up in the urine(.61*.77=.47).

d} Would you consider the oral forms bioequivalent? (No)

Why/Why not? Ratio of peak times ouside guidelines.

e} What infusion rate would you suggest to maintain a plasma concentration of0.75 mic/ml ?

Q = Cpss * K * V = 0.75 mg/L * 0.283 hr^-1 * 125 L = 26.54 mg/hr

f} How long would it take that infusion to attain a therapeutic plasma concentra-tion of 0.5 mic/ml ?

Cp = Q/(K*V)(1-exp(-K*T) = 0.5 = 26.54/(0.283*125)*(1-exp(-0.283*T)) --> 3.9hr

4) LYSERGIC ACID DIETHYLAMIDE (LSD) was given to human volunteers atthe dose of 150 mic orally. (Impregnated blotter dosage form.) The following datawas obtained:

Oral Dosing


Time Cp (ng/ml) Time Cp (ng/ml)

0.25 1.75 2.0 4.6

0.5 2.9 3.0 4.1

0.75 3.7 4.0 3.3

1.0 4.2 6.0 2.1

1.5 4.6 8.0 1.4

a) Find ka

b) An IV dose of 100 mic resulted in an AUC of 20.4 ng/ml*hr. Find f.

c) The volunteers ability to concentrate as measured by their ability to do standardtasks was also monitored. (100% control means no drug interference.) The fol-lowing data was obtained:

Cp (ng/ml) % Control Cp (ng/ml) % Control

5.5 33 1.5 65

4.1 40 1.1 80

2.9 52

If 100 mic dose were given by IV bolus, how long would it be before the volunteerwould regain 80% of his control?

Answwer:

Oral Dosing


Evaluation of the graph of Concentration vs. time yields:

Cpmax 4.63 ng/mL

T max 1.7 hr

AUC (trap)30.07

K 0.225 hr^-1

Oral Dosing


m (-K) -0.225 hr^-1

Ka 1.22 hr^-1

f (AUCoral/Doseoral)/(AUCiv/Doseiv) = .98

Evaluation of the graph of response vs ln(concentration) yields:

dR/dln(c) = 27.86

Multiplying dR/dln(c) * dln(c)/dt (m of the previous graph) yields dR/dt = 27.86 *-0.225 = 6.26%/hr

100 mic dose IV yields Cp0 of (Cp0 =AUC * K = 20.4 * 0.225) 4.59ng/mL.

The response of a 100 mic dose is (R = 27.86*ln(4.59)+19.9) 62.3%

Response = Response at t=0 - dR/dt * t

20% = 62.3% - 6.26%/hr * t hours

T = 6.76 hours

5. The following data was collected from a double blind cross over study between500 mg dose of cloxacillin made by Bristol (Tegopen@) and a generic productwhich you might want to put in your store.

Time (Conc. mic/ml) Time (Conc. mic/ml)

TEGOPEN GENERIC TEGOPEN GENERIC

Oral Dosing


0.25 .41 0.1 1.5 6.93 7.75

0.5 8.56 6.39 2 4.95 5.16

0.75 11.97 11.44 3 2.19 2.29

1 11.28 11.42 4 1.48 1.30

1.25 9.57 9.64

Calculate the comparative bioavailability.

Would you consider these products bioequivalent? Why/Why not?

Answer:

Oral Dosing


Evaluation of the above graphs yields:

Tegopen GenericRatio (G/T)

Cpmax (mic/mL)10.8 9.94 0.92

T max (hr) 0.74 0.89 1.20

AUC (trap) 21.7 21.06 0.97

K (hr^-1) 0.72 0.8

ka (hr^-1) 4.3 2.69

Actual evaluation of ka and peak time is dificult because of the pucity of data atearly time points however all relavent parameters meet guidlines.

7. The F.D.A. reported the following data submitted to be consideration regardingthe equivalence of Mylan Pharmaceuticals' Tetracycline with that of Lederle andan intervenous bolus dose. (Dose 250 mg).

Time(hrs) Conc.(mcg/ml) Time(hrs) Conc.(mcg/ml)

Lederle Mylan I.V. Lederle Mylan I.V.

0.5 0.55 0.20 5.2 4 2.70 2.60 2.9

1 1.80 1.35 4.8 6 2.20 1.80 2.1

1.5 2.11 1.75 4.4 9 1.35 1.25 1.26

2 2.35 2.10 4.0 12 0.83 0.74 0.76

Oral Dosing


3 2.65 2.25 3.4 15 0.50 0.45 0.46

Would you consider Mylan to be bioequivalent to the Lederle product ?

Calculate the absolute bioavailability of Lederle Tetracycline.(.77)

f) Calculate the volume of distribution of tetracycline. (44.3 L)

g) Tetracycline has a pKa of 9.7. Tetracyclines tend to localize in the dentin andenamel of developing teeth causing hypoplasia and permanent discoloration ofteeth. Would you recomend tetracyline for a 110 pound lactating mother ?

Support your argument with the dose of the child. (Child's weight 11 lbs. and heeats 2 oz of milk every 2 hours. Mom's average plasma concentration is main-tained at 3 mic/ml by taking 250 qid. pH of the milk is 6.1, pH of blood is 7.4)

Answer:

Oral Dosing


Pharmacokinetic parameters:

Lederle Mylan IV

Cpmax (mic/mL)2.75 2.42 5.65

Tmax (hr) 3.04 3.08 0

AUC 26.4 23.3 31.4

k (hr^-1) 0.165 0.161 0.167

Ka (hr^-1) 0.684 0.729

Ratio of bioequivalence parameters (Cpmax, Tmax and AUC) are all within guide-lines. So, the would be considered bioequivalent.

Absolute bioavailability f (= (AUCoral/DOSEoral)/(AUCiv/DOSEiv) = (26.4/250)/(31.4/250) is 0.84.

Oral Dosing


Volume of Distribution (Dose/Cp0 = 250 mg/ 5.65 mg/mL) is 44.2 L

The ratio of milk to blood is about 200.

r(m/b) = (10^(pKa-pH) + 1)milk / (10^(pKa-pH) + 1)blood

= (10^(9.7-6.1)+1)/(10^(7.4-6.1)+1) = 10^3.6/10^1.3 = 10^2.3 = 200

Dose the kid gets is mom's plasma concentration * Ratio(M/b) * volume of milk /day = 3 mic/mL * 200 * 60cc * 12 feedings = 432 mg.day

Mom gets 1000 mg/day

Ratio of dose on a mg/kg basis (kid/mom) = (432/5)/1000/50) = 4.32 - Kid's get-ting more than mom.

Fifty miligrams of ketameperidine was given by IV bolus. The following urinaryprofile was obtained for the only metabolite N-methyl-ketameperidine:

Collection period (hr) Mean urinary excretion rate (mg/hr)

0.0 - 0.5 2.26

0.5 - 1.5 5.83

1.5 - 2.5 5.43

2.5 - 3.5 4.60

3.5 - 5.0 2.36

Oral Dosing


5.0 - 7.0 1.47

7.0 -10.0 0.96

10.0 -18.0 0.44

Calculate K, km and ku.

What Percent of ketameperidine was metabolized?

Answer:

With only one data point in the early time points, the larger rate constant is in ques-tion. The terminal slope is assumed to be K. The AUC will yield the amount ofketameperidine which was metabolized (dXmu/dt * t = Xmu).

K (hours^-1) 0.216

AUC (mg)30.3

30.3 mg showed up as metabolite = 60.6% of 50 mg dose.

km = 60.6% * K = 0.131 hours^-1

Oral Dosing


kr = K - km = 0.085 hours^-1

Aminophylline consists of THEOPHYLLINE (85% W/W) & Ethylene diamine(15% W/W)

THEOPHYLLINE is the active compound measured in blood.

THEOPHYLLINE has a volume of distribution of 0.45 l/kg.

THEOPHYLLINE is 10% excreted unchanged and 90% metabolized to inactivemetabolites.

THEOPHYLLINE has a therapeutic range between 20 and 10 mg/l.

AUC FROM 0 to infinity for THEOPHYLLINE (given as 400 mg AMINPHYL-LINE) is 120 mg/l x hr.

The average plasma concentration of THEOPHYLLINE given as 400 mg of AMI-NOPHYLLINE is as follows:

time conc. time conc.

(hrs) (mg/L) (hrs) (mg/L)

0.5 7.24 4.0 8.06

1.0 9.56 6.0 6.89

2.0 10.00 8.0 5.57

3.0 8.84 10.0 4.53

Find f, K, ka, Vd,total body clearance.

Find the infusion rate necessary to maintain a plasma concentration of 15 mg/l.

Oral Dosing


Answer:

AUC (mg/L)*hr117.8

K (hr^-1) 0.096

ka (hr^-1) 2.11

f = (AUCoral/DOSEoral)/(AUCiv/DOSEiv) =

= (117.8 / 400 )/(120 / 400 ) = 0.98

Vd

AUC * K = Cp0iv

120 * 0.096 = 11.52 mg/L

Vd = Dose/Cp0 = (400mg*0.85)/11.52 = 29.5 L

TBC = K * Vd = 0.096/hr * 26.5L = 2.83 L/hr

Oral Dosing


Infusion rate = Q = Cpss * TBC = 15 mg/L * 2.83 L/hr = 42.45 mg/hr Theophyl-line = 42.45/.85 = 50 mg/hr Aminophylline

Abbott labs has provided the following data conserning their ORETIC tablets(hydrochlorthiazide tablets U.S.P.) Dose given was 50 mg.

time conc. time conc.

(hrs) (mg/L) (hrs) (mg/L)

0.5 0.05 3.0 0.31

1.0 0.21 4.5 0.23

1.5 0.27 6.0 0.18

2.0 0.31 8.0 0.12

a Find K, ka, Cmax,

Answer:

Oral Dosing


The data is plotted both without (first figure) and with (second figure) a lag-timewhich is associated with the release of the drug from the delivery system. Notethat the addition of the lag-time improves the fit.

The parameters obtained from each fit are:

WithoutWith

Cpmax (mg/L)0.22 0.31

Tmax (hr) 3.45 2.28

AUC (mg/L*hr)2.2 2.26

K (hr^-1) 0.216 0.201

ka (hr^-1) 0.380 1.10

t lag (hr) 0.0 0.393

Oral Dosing


It takes the tablet about 20 minutes to release the drug!

Wilkenstein et al.(Gastroenterology 74:360,1978) tested 12 normal healthy volun-teers in a four way crossover design of four dosage forms containing 300 mg ofcimetadine. The following data was obtained: A B C D

AUC(mic/ml x hr) --- --- 5.2 5.4

recovered in urine intact77.177.1 54.9 55.8

Peak serum conc.(mic/ml)--- --- 1.53 1.44

Onset (hr) 0 0.34 0.65

Duration (hr) 4.5 4.6 4.2 4.4

Time to peak (hr) 0 1.0 2.0

A = IV Bolus B=IM injection C = Oral liquid D= Oral tablet

The plasma concentration vs. time profile for product A is as follows:

time (hrs) conc.(ug/ml)

1 1.79

2 1.36

4 0.78

6 0.45

12 0.08

a} find K, Cp0.

Both can be found from the graph. K = .283/hr Cp0 = 2.36 mic/ml

Oral Dosing



5.2/8.5 = 0.61


Very well. Only 61% (f) of liquid gets in and you would expect only 77% of thatto show up in the urine because only 77% of the IV dose shows up in the urine(0.61 * .77 = .47).

d} How can you explain the variation in % recovered intact in the urine?

e} Would you consider the oral forms bioequivalent ? Why/Why not?

No. The ratio of peak times is outside the guidelines.

f} What infusion rate would you suggest to maintain a plasma concentration of0.75 mic/ml?

Q = Cpss * K * V = 0.75 mg/L * 0.283/hr * 125L = 26.54 mg/hr

g} How long would it take that infusion rate to attain a therapeutic plasma concen-tration of 0.5 mic/ml ?

Cp = Q/(K * V)(1-exp(-K*T) = 0.5 = 26.54/(0.283 *125)*(1-exp(-0.283 * T)) -> 3.9 hr

Roxane labs of Columbus, Ohio offers the following data for your review of theirQuinidine Sulfate tablets (Dose 200 mg). It is compared against the referencestandard by Ely Lilly and company at the same dose.

Oral Dosing


Time (hours)Concentration (mcg/ml)

Roxane Lilly

1 .42 .58

2 .73 .77

3 .71 .74

4 .61 .66

6 .45 .52

8 .32 .34

12 .20 .22

a) Calculate the comparative bioavailability.

b) Would you consider Roxane Quinidine Sulfate to be bioequivalent to the Lillyproduct ?

Answers

Oral Dosing


Oral Dosing


Roxane labsEli Lilly

w/o w w/o w Rw/o(R/L)Rw(R/L)

Cpmax (mcg/mL)0.650.740.740.76 0.88 0.97

AUC (mcg/mL*hr)6.086.236.756.84 0.90 0.91

Tmax (hr) 2.69 2.05 2.33 2.10 1.15 0.98

T lag (hr) 0.0 0.70 0.0 0.36

Yes. Ratios are within guidelines.

Shand et al. offers the following data for propranolol : Answers:

Time Concentration (ng/ml)

(hours)10 mg I.V. 80 mg oral

0.5 -- 50

1 -- 77

1.5 -- 100

2 29 100

3 24 90

4 18 78

5 15 59

6 11 45

7 9 32

Oral Dosing


a) find ka

b) Calculate the absolute bioavailability of propranolol.

c) Calculate TBC

Oral Dosing


IV data Oral Data

w/o w

AUC (ng/mL*hr)201.3562.8 540

Cpmax (ng/mL) 47.7 97.8 99.7

Tmax (hr) 0 2.0 2.1

K (hr^-1) 0.239 0.324 0.421

ka (hr^-1) --- 0.715 0.548

T lag 0.0 0.02

Absolute bioabailability = (AUCoral/DOSEoral)/(AUCiv/DOSEiv)

= (562.8/80) /(201.3/10) = 0.35 or using lag time data

(540 / 80) /(210.3/10) = 0.335

TBC = Dose / AUC = 10,000 mic/ 201.3 mic/L*hr = 50 L/hr or

0.35*80,000mic /562.8 mic/L*hr = 50 L/hr

Niazi et al. offers the following data for meperadine :

Meperidine : is 95% metabolized

has an absolute bioavailability of 0.4

has a hepatic plasma extraction ratio of 0.6

has a volume of distribution of 100 L.

has a half life of 3.5 hours.

Oral Dosing


a) Calculate TBC

TBC = K * V = (0.198/hr)(100L) = 19.8 L/hr

b) Calculate the intrinsic hepatic plasma clearance of meperidine.

19.8 L/hr * .95 = 18.8 L/hr

c) Calculate the effect on total body clearance in a patient with viral hepititis (FI =0.3).

Clh*/Clh = (.3)(1)/1 + .6(.3 - 1) = .3/.58 = .517

(.517)(18.8) = 9.72

TBC = 1 + 9.72 = 10.72

d) Calculate the effect on total body clearance in a patient with stenosis (FR = 0.3).

Clr*/Clr = (1)(.3)/.3 + .6(1 - .3) = .3/.72 = .417

TBC = 18.8 + .417 = 19.22

e) Comment on which patient might need modification in therapy and why.

The patient with viral hepatitis would need modification in therapy. Becauseof the decrease in TBC, we can see that the drug is staying the body muchlonger than normal, therefore the dosage regimen should be decreased.

Chlorthalidone is used to treat high blood pressure. The following information isoffered regarding a generic

and a brand name chlorthalidone 50 mg tablet:

Time Conc. (mcg/ml)

Oral Dosing


(hours) Hygroton@Generic

.5 0.14 0.15

1 0.51 0.64

2 1.23 1.67

3 1.94 2.48

4 2.20 2.91

6 2.64 3.49

8 2.86 3.52

12 3.43 3.82

24 3.22 3.38

48 2.45 2.74

72 1.53 1.91

96 1.20 1.40

120 0.76 0.77

Pharmacokinetic parameters

Cpmax (mg) 3.73 4.62

Time to peak (hr) 13.810.8

AUC (0 to Inf)293 336

Xu inf (mg)18.3 22.1

Ka (hr^-1)0.168 0.253

Ke (hr^-1)0.019 0.019

Oral Dosing


Average mean83.1 84.5

blood presure

a) Calculate the comparative bioavailability.

(336/50mg)/(293/50mg) = 1.15

b) Would you consider the generic product to be bioequivalent to the USV(Hygroton@) product? Prepare a short statement that you would tell a patientregarding why you would or would not make a generic substitution for this drug.

No. The maximum concentration the generic is too much greater than that ofthe brand name product.

They are not considered to be bioequivalent.

R(G/H)

Cpmax (mg) 1.23 outside

Time to peak (hr)0.78outside

AUC (0 to inf)115 ok

Buspirone is a new anxiolytic agent that has been found to be effective for thetreatment of generalized anxiety disorder at a mean dose of approximately 20 mg/day orally in divided doses. Buspirone is metabolized almost entirely. Less than0.1% is found intact in the urine. The following data has been presented by Gam-mans (Am J Med:80(supp 3b),41-51;1986):

Time (hours)Concentration (ng/ml)

(hours) 1 mg I.V.20 mg oral

Oral Dosing


0.25 -- 1.07

0.50 4.33 1.76

1.0 3.75 2.45

2 2.80 2.51

3 2.10 2.05

4 1.57 1.60

6 0.8 0.91

a) find ka

b) Find Oral Peak Time and Oral Cmax.

c) Calculate the absolute bioavailability of buspirone.

answer:

Oral Dosing


IV Oral

Cpmax (ng/mL) 5.0 2.6

AUC (0 to inf)17.4 13.9

Tmax (hr) 0 1.5

K (hr^-1) 0.290 0.289

ka (hr^-1) 1.3

Absolute bioavailability, f, = (AUCoral/DOSEoral)/(AUCiv/DOSEiv)

= ( 13.9 / 20) /( 17.4/ 1 )

= 0.04

Valproate is a carboxylic acid anticonvulsant. Its activity may be related, at leastin part, to increase concentrations of the neurotransmitter inhibitor gamma ami-nobutyric acid in the brain. It is used alone or in combination with other anticon-vulsants. in the prophylactic management of petit mal. It appears to be almostentirely cleared by liver function with negligible amounts excreted into the urineunchanged. It comes as soft gelatin capsules of 250 mg and enteric coated tablets250 and 500 mg as well as oral syrup of 250 mg / 5 cc. Two different formula-tions of Valproate (250 mg) were prepared by Abbott and compared. The data is asfollows:

Oral Dosing


Time(Hr.)Formulation BFormulation A

0.5 3.4 AUC = 287 mg/L * hr

1.0 6.0 Ka = 0.7 hr^-1

1.5 7.9 Ke = 0.065 hr^-1

2.0 9.3

2.5 10.3

3.0 10.9

4.0 11.6

6.0 11.4

8.0 10.5

12.0 8.3

18.0 5.7

24.0 3.8

1) find ka for formulation B.

2) Five hundred mg of valproate was administered by IV bolus. The AUC for thatroute was 574 mg/L * hr. Calculate f for formulation A. Calculate Cp0 for the IVdose.

3) Find Peak Time and Cmax for formulation A.

4) Calculate the comparative bioavailability of formulation B.

5) Would you consider formulation B to be bioequivalent to Formulation A ? Pre-pare a short statement in which you would substantiate that stand that you might

Oral Dosing


need to respond to another health professional who asked you to stock that formu-lation for his patients.

6) Calculate the Total Body Clearance (TBC) of valproate.

Answers:

Formulation B R(A/B)

AUC = 243.3 mg/L * hr 1.18

Cpmax = 11.7 mg/L1.12

Tp max = 4.70 hr0.79

ka = 0.493 hr^-1

K = 0.0655

Tmax(A) = ln(ka/K)/(ka-K)= 3.75 hr

cpmax =

(ka/(ka-k))*(fX0/Vd)*(exp(-k*tmax)-exp(-ka*tmax)

13.3 mg/L

Absolute bioavailability, f,=(AUCoral/DOSEoral)/(AUCiv/DOSEiv)

= (287/250)/(574/500)

= 1.0

Oral Dosing


Comparative bioavailability =(AUCb/DOSEb)/(AUCa/DOSEa) = 243.3/287 =0.85

TBC = Dose / AUC = 500 mg / 574 mg /L * hr

The following data was made available by Lederle Labs regarding its genericProcainamide HCl. (Dose 250mg).

Procainamide is a base (pka =9.1). As the hydrochloride salt it is 87% Procaina-mide.

Time (hrs)Conc.(mcg/ml) Procainamide Base

Lederle Squibb I.V.

0.33 0.68 0.26

0.5 0.82 0.67

0.66 1.17 0.93

1 1.23 1.12 1.45

1.33 1.31 1.19 1.35

2 1.39 1.12 1.18

3 0.93 0.96 0.95

4 0.74 0.74 0.77

6 0.51 0.51 0.51

8 0.32 0.30 0.33

12 0.11 0.09 0.14

Oral Dosing


a) find ka of the Squibb product

b) ka of the Lederle product.

c) Calculate the comparative bioavailability.

d) Would you consider Lederle to be bioequivalent to the Squibb product ?

e) Calculate the absolute bioavailability of Lederle Procainamide.

f) Calculate the volume of distribution of procainamide.

g) Would you recommend your patient breast feed her newborn? Prepare a shortconsult for her physician. Support your argument with the dose of the child.(Child's weight 11 lbs. and he eats 2 oz of milk every 2 hours. Mom's averageplasma concentration is maintained at 4 mic/ml from a 1 g dose ever 6 hours. pH ofthe milk is 6.3, pH of blood is 7.4)

Procainamide is cleared about 60% by liver and 40% by kidney function. 20 % ofcardiac output (70 ml/min/kg) goes to liver, 25% goes to the kidney. Mom'sweight is 130 lb. Assuming her plasma vs time profile to be similar to the Lederleproduct (i.e. pharmacokinetic parameters obtained from this information can beused):

h) Calculate Total body clearance

i) Calculate the intrinsic hepatic plasma clearance of procainamide.

j) Calculate the effect on her total body clearance if she were to contract viral hep-atitis which effect liver function (FI = 0.4). Prepare a short consult for her physi-cian as to whether you would recommend a change in therapy. d) Calculate theeffect on her total body clearance stenosis of the liver (FR = 0.4). Prepare a shortconsult for her physician as to whether you would recommend a change in therapy.

Answers:

Oral Dosing


IV LederleSquibbR(L/S)

AUC (0 to inf)8.577.46.8 1.09

Cpmax 1.8 1.28 1.25 1.02

Tmax 0 1.43 1.45 0.99

K 0.212 0.247 0.256

ka --- 1.51 1.93

t lag 0 0 0.24


= 7.4 / 8.57

Oral Dosing


= 0.86

Vd = Dose/Cp0 = 0.87*250mg/1.8mg/L= 120.8 L

Ratio of milk to blood = (10^(9.1-6.3)+1)/(10^(9.1-7.4)+1)= 12.4

Kid's dose = 4 mic/mL * 12.4 * 60 mL/feeding * 12 feedings/day * 1 mg/1000 mic= 36 mg/day

Ratio of kid's daily dose/# to Mother's daily dose/# = (36mg/11#)/(1000mg*4/130#) = 0.42. The kid gets about half of the mother's dose!

Nifedipine (Procardia @) is a calcium channel blocker which specifically inhibitspotential-dependent channels not receptor-operated channels, preventing calciuminflux of cardiac and vascular smooth muscle (coronary, cerebral). Calciumchannel blockers reduce myocardial contractility and A-V node conduction byreducing the slow inward calcium current. They are indicated in angina, cardiacdysrhythmias, and hypertension among others. Nifedipine appears to be metabo-lized entirely into an inactive metabolite, an acid and subsequently further metab-olized to a lactone. Both the acid and the lactone are excreted into the urine andthe feces.

Echizen and Eichelbaum (Clin Pkin 1986; 11:425-49) and Kleinbloesem et al (ClinPcol Therap 1986; 40: 21-8) Reviewed the pharmacokinetics of Nifedipine. Whilethe drug is not routinely given by IV bolus and does not strictly conform to a onecompartment model, lets treat the data as if those problems can be ignored. Thefollowing data is offered for evaluation:

25mg IV 10 mg oral tablet

Formula AFormula B

Time Cp Cp Cp

Oral Dosing


(hr.) (mic/l) (mic/l) (mic/l)

0.5 29.3 33.1

1 42.1 43.7

1.5 45.7 43.7

2 139 44.4 39.8

3 36.2 25.5

4 65.6 27 20.7

6 31.1 13.6 9.9

8 14.6 6.5 4.7

12 1.5 1.0

a} Find ka's of the two products.

b} Calculate peak time and Cp max for both products.

d} Can you conclude that these products are bioequivalent ? (you must support youargument)

e) Calculate the absolute bioavailability of product A.

f} What infusion rate would you suggest to maintain a plasma concentration of 30mic/L ?

Answers:

Oral Dosing


IV A B R(A/B)

Cpmax (mic/L)294.25 45.7 44.01.04

Tmax (hr) 0 1.57 1.18 1.33

AUC(0 to inf)785219.7182.7 1.20

ka (hr^-1)--- 1.0 1.6

K (hr^-1) 0.375 0.374 0.375

No,Tmax is outside the guidelines.

Oral Dosing



=(219.7/10)/(785/25)

=0.7

Q = Cpss * K * V = 0.955 mg/hr

Tetracycline HCl has a pKa of 9.7. Tetracyclines tend to localize in the dentin andenamel of developing teeth causing hypoplasia and permanent discoloration ofteeth. Would you recommend tetracycline for a lactating mother ? Support yourargument with the dose of the child. (Child's weight 11 lbs. and he eats 2 oz ofmilk every 2 hours. Mom's average plasma concentration is maintained at 4 mic/ml she is taking 250 mg T.I.D. ( Milk pH = 6.1, Blood pH = 7.4)

Tm/Tb = 109.7 - 6.1/109.7 - 7.4 = 20/1

The concentrarion of tetracycline in the mother's milk is 80 mic/ml

The child takes in 720 ml of milk per day

80 mic/ml * 720 ml = 57600 mic = 57.6 mg

57.6mg/5kg = 11.52mg/kg = dose that the child is getting from the mother'smilk.

I would not recomend tetracycline for a lactating mother. The dose that a nurs-ing child gets from the milk too high.

Oxazepam (acid, pKa 11.5) is an anxyolytic sedative with the usual adult dose 10mg 3 times daily. If the circulating plasma concentration of oxazapam were 20

Oral Dosing


mic/ml for nursing 120 lb mother, would her 9 lb infant be getting a comparablemg per kg daily dose if he consumes 2 oz of his mothers milk every 2 hours. Pre-pare a short consult for her physician in which you might (or might not) recom-mend the patient stop breast feeding while she is on this medication. Includeappropriate calculations.

Om/Ob = 1011.5 - 6.1/1011.5 - 7.4 = 20/1

The concentration of the mother's milk would then be 400 mic/ml

400 mic/ml * 720 ml = 288000 mic given to baby = 288mg

288mg / 4.1kg = 70 mg/kg = dose/kg given to baby

This dose is much greater then that given to the mother. The mother shoulddiscontinue breast feeding while taking Oxazepam.

Bioequivalence studies are sometimes done within the same company to check ifthe tablets of the same drug, but different strengths (with the strength normalized)could be considered equivalent (i.e. could two 5 mg tablets be considered equal toone 10 mg tablet). While not strictly kosher (products are not pharmaceuticalequivalents because of different strengths), it is done. Here is the results of such astudy in which Zomax 100 and 200 mg tablets were compared. (Yes, I know thatZomax was removed from the market after a short life of only 6 months.)

Zomax 100 mg tablet 200 mg tablet 50 mg IV bolus

Time Conc AUC Conc AUC Conc.

(hr) (mg/L) (0->t) (mg/L) (0->t) (mg/L)

0.25 1.41 0.18 4.03 0.50

0.5 1.98 0.60 5.13 1.65

0.75 2.15 1.12 5.18 2.94

1 2.12 1.65 4.89 4.20 1.14

Oral Dosing


2 1.56 3.49 3.37 8.33 0.764

3 1.05 4.80 2.26 11.14 0.512

4 0.707 5.67 1.51 13.03 0.343

6 0.318 6.70 0.68 15.22 0.154

8 0.143 7.16 0.306 16.20 0.069

1) What is the elimination rate constant for zomax (hr) ?

A) 0.2 B) 0.3 *C) 0.4 D) 0.5 E) 0.6

2) What is the volume of distribution of zomax given by IV bolus (L) ?

A) 43.85 B) 33.3 *C) 29.4 D) 25.9 E) 0.034

AUC = D/(Vd * K)

Vd = D/(AUC * K)

= 50mg/(4.25 * 0.4)

= 29.4 L

3) What is the volume of distribution of zomax given by 100 mg oral tablet ?

A) 43.85 *B) 33.3 C) 29.4 D) 25.9 E) 0.034

Vd = 100mg/(7.48 * 0.4)

= 33.4 L

Oral Dosing


4) What is the AUC(0->infinity_ for the IV bolus dose ?

A) 2.68 B) 2.85 C) 3.55 D) 4.08 *E) 4.25

5) What is the AUC(0->infinity) for the 100 mg tablet ?

A) 7.16 *B) 7.5 C) 16.20 D) 17 E) 37.38

6) What is the absolute bioavailability of the 100 mg tablet ?

A) 0.84 *B) 0.88 C) 1 D) 1.14 E) 1.19

(7.48/100)/(4.25/50) = 0.88

7) What is the AUC(0->infinity) for the 200 mg tablet ?

A) 7.16 B) 7.5 C) 16.20 *D) 17 E) 73.98

8) What is the absolute bioavailability of the 200 mg tablet ?

A) 0.84 B) 0.88 *C) 1 D) 1.14 E) 1.19

(16.9/200)/(4.25/50) = 1

9) What is K * AUC (0->infinity) for the 100 mg tablet (mic/ml) ?

A) 2.9 *B) 3.0 C) 6.5 D) 6.8 E) 14.95

7.48 * 0.4 = 2.99

Oral Dosing


10) What is the absorption rate constant for the 100 mg tablet ?

A) 1.7 B) 2.2 *C) 2.6 D) 3.2 E) 3.7

11) What is the intercept of the extrapolated line for the 200 mg tablet ?

A) 3.5 B) 4.1 C) 5.6 D) 6.1 *E) 7.6

12) What is the absorption rate constant for the 200 mg tablet ?

A) 1.7 B) 2.2 C) 2.6 D) 3.2 *E) 4.01

13) What is the Tmax for the 100 mg tablet ?

A) 0.5 B) 0.67 C) 0.75 *D) 0.85 E) 0.95

14) What is the Tmax for the 200 mg tablet ?

A) 0.5 *B) 0.67 C) 0.75 D) 0.85 E) 0.95

15) Would you consider these two tablets bioequivalent (given normalization fordose) (consider all ratios to be the 100 mg / 200 mg parameter normalized as todose where applicable)?

A) Yes

B) No, because the ratio of the ka's is 0.70

C) No, because the ratio of the AUCs is 0.44

Oral Dosing


D) No, because the ratio of the Cmaxs is 0.41

*E) No, because the ratio of the Tmaxs is 1.27

16) What infusion rate would you recommend to maintain an average plasma con-centration of 1 mic/ml ?

A) 17.5 B) 13.3 *C) 11.8 D) 10.4 E) 9.0

Vd = D/Cp0 = 50mg/1.7mg/L = 29.4

Q = Cpss * K * V = 1mg/L * 0.4/hr * 29.4L = 11.8

17) What would be the concentration (mg/L) 2 hrs after discontinuing the infu-sion assuming you reached steady state ?

A) 0.67 B) 0.55 *C) 0.45 D) 0.37 E) 0.30

Cpss = Cp0 * e-Kt

= 1mg/L * e(-0.4 * 2)

= 0.44

A 110 pound mother breast feeds her 11 pound infant while on morphine sulfate(base, pKa = 9.85). Mother's average circulating plasma levels are 0.5 ug/ml fol-lowing a 10 mg IV dose q4h. (pH Milk = 6.1, pH blood = 7.4)

18) What is the Ratio of morphine concentration in the milk as compared to theblood ?

A) 0.05 B) 0.5 C) 1 D) 2 *E) 20

Oral Dosing


Mm/Mb = 10(9.85 - 6.1)/10(9.85 - 7.4)

= 20

19) How much (mg) morphine is contained in 120 cc of breast milk (the child con-sumes 2 ounces every 2 hours) *A) 1.2 B) 0.12 C) 0.06 D) 0.03 E) 0.003

Mother's blood conc. is 0.5mic/ml therefore her milk conc. is 10 mic/ml.

10mg/L * 0.12L = 1.2 mg

20) In your professional judgment, will the child's dose cause a problem ?

A) No, morphine does not concentrate in the milk and thus the milk is ok to drink.

B) No, the dose is too small. The ratio of the child's dose to the mother's dose is0.12.

C) Yes, even though the dose is small, we don't want any drug to get to the child.

*D) Yes, the dose is comparable to the mother's dose. The ratio of the child's to themother's dose is 1.2.

E) Not my job. I only give what the doctor orders.

Answers:

Oral Dosing


IV Tablet Tablet

50 mg 100 mg200 mgR(100/200)

AUC(0 to inf)4.257.4816.9 0.89

Cpmax 1.7 2.15 5.23 0.82

Tmax 0 0.82 0.64 1.28

K 0.4 0.4 -.4

ka --- 2.76 4.01

Tmax ratio is ouside guidelines.

Oral Dosing


Answers are rounded off. When you pick a foil, use that number in subsequent cal-culations when needed.

Rifampin (unionized free base pKa 7.9) is a drug used to treat TB. The followingdata was collected following a 600 mg oral tablet from the inovator (Treatment A),and a 600 mg oral tablet from a generic (treatment B), and a 400 mg IV dose(Treatment C).

Concentration (mic/mL)AUC(0->t)

TreatmentA B C B

Time (hours)

0.5 5.3 4.8 1.2

1 10.3 8.6 7.8 4.55

1.5 10.2 9.8 9.15

2 9.4 9.8 6.1 14.05

2.5 8.9 9.2 18.8

3 7.5 8.4 4.7

4 5.9 6.7 3.7

6 3.6 4.1 2.2

8 2.2 2.5 1.3

10 1.3 1.5 0.8

12 0.8 0.92 0.5

AUC(0->inf)53.957.7

Oral Dosing


(mic/mL*hr)

Lag time (min)18.610.5

Cp max10.6 9.9

Ka (hr^-1)2.66

1) What is the Cp0 for C (mg/L)? a) 0 b) 7.8 *c) 10 d) 12 e) 15

Cp0 = AUC * K

= 39.8 * 0.25

= 9.95

2) What is the volume of distribution of Rifampin (L)? a) 60 b) 51.3 *c) 40d) 33.3 e) 26.7

Vd = D/Cp0

= 400mg/(9.95mg/L)

= 40.2 L

3) What is the half life for rifampin (hr)? *a) 2.8 b) 2.3 c) 2.0 d) 1.75 e)1.5

t1/2 = .693/0.25

= 2.77

Oral Dosing


4) What is the elimination rate constant for rifampin (hr^-1)? *a) 0.25 b) 0.3 c)0.35 d) 0.4 e) 0.45

5) Calculate the AUC (0->1hr) for C (mic/mL*hr). a) 1.95 *b) 3.9 c) 7.8 b)8.9 e) 17.8

6) Calculate the AUC (12hr->inf.) for C (mic/mL*hr). *a) 2 b) 1.67 c) 1.43d) 1.25 e) 1.11

0.5/0.25 = 2

7) Calculate the AUC (0->inf) for C (mic/mL*hr). a) 16 b) 26.85 c) 35 *d)40 e) 60

8) Calculate the absolute bioavailability for the generic product. a) 0.70 *b)0.95 c) 1 d) 1.05 e) 1.43

(57.7/600)/(39.8/400) = 0.966

9) Calulate the comparative bioavailability for the generic product. a) 0.70 b)0.95 c) 1 *d) 1.05

e) 1.43

(57.7/600)/(53.9/600) = 1.07

10) Using Wagner-Nelson method, calculate the Ka for the generic product (hr^-1). a) 0.45 b) 1 c) 1.55 d) 2 e) 2.45

Oral Dosing


11) Calculate the peak time for the generic product (min). a) 37 b) 67 c) 86 d)91 e) 105

tp = [ln(Ka/K)]/(Ka - K)

= [ln(1.37/0.25)]/(1.37 - 0.25)

= 1.52 hr = 91 min

12) Calculate the peak time for the brand name product (min). a) 37 *b) 59 c)86 d) 95 e) 105

tp = [ln(2.66/0.25)]/(2.66 - 0.25)

= 0.98 hr = 59 min

13) Are the two products bioequivalent?

a) yes, all federal requirements are met.

*b) no, the ratio of the peak times are out side federal requirements.

c) no, the ratio of the lag times are out side federal requirements.

d) no, the ratio of the Kas are out side federal requirements.

e) no, the ratio of the comparative bioavailabilities are out side federal require-ments.

14) What is the ratio of the concentration of milk (pH 6.1) to blood (pH 7.4)? a)0.05 b) 0.05 c) 1 d) 15.4 *e) 20

Rm/Rm = 10(7.9 - 6.1)/10(7.9 - 7.4)

Oral Dosing


= 20

15) The average plasma concentration for the mother (110#) is 2.5 mg/L from a600 mg once a day dosing regimen. If the baby (11#) drinks 780 mL of milk a day(2 - 2.5 ounces every 2 hours), what is his daily dose (mg)?

a) 0.1 b) 0.13 c) 2 d) 30 *e) 39

Mother's blood average blood conc. is 2.5 mg/L therefore her milk conc. is 50mg/L.

If the baby drinks 780 ml of milk he/she will get 39 mg of the drug.

16) Would you recommend mom stop breast feeding? (What % of the mom's dailydose (mg/kg) is the baby's daily dose (mg/kg)?)

a) No, the child's dose is less than 1% of the mother's dose on a mg/kg/day basis.

b) No, the child's dose is about 5% of the mother's dose on a mg/kg/day basis.

c) Maybe, the child's dose is about 10% of the mother's dose on a mg/kg/day basis.

*d) Yes, the child's dose is about 50% of the mother's dose on a mg/kg/day basis.

e) Yes, the child's dose is about the same as the mother's dose on a mg/kg/daybasis.

17) While Rifampin is not administered by IV infusion, what would be the infu-sion rate necessary to maintain an average plasma concentration of 2.5 mg/L (mg/hr)? *a) 25 b) 50 c) 100 d) 150 e) 200

Vd = D/Cp0

= 400/10.02

= 39.9 L

Oral Dosing


Q = Cpss * K * Vd

= 2.5 * 0.25 * 39.9

= 25 mg/hr

18) While Rifampin is not administered by IV bolus, what would be the loadingdose necessary to obtain a plasma concentration of 2.5 mg/L (mg)? a) 25 b) 50*c) 100 d) 150 e) 200

Loading Dose = Cpss * Vd

= 2.5 * 39.9

= 100mg

19) While Rifampin is not administered by IV infusion, what would be the infu-sion rate necessary to obtain a plasma concentration of 2.5 mg/L in about 2.5 to 3hours (mg/hr)? a) 25 *b) 50 c) 100 d) 150 e) 200

Cp = [Q/(K * Vd)] * (1 - e-kt)

Q = (Cp * K * Vd)/(1 - e-kt)

= (2.5mg/L * 0.25 * 39.9L)/[1 - e(-0.25 * 2.75)]

= 50 mg/hr

20) Rifampin is a semisynthetic derivative of rifamycin B, an antibiotic derivedfrom Streptomyces mediterranei. The minimum inhibitory concentration for N.menengitidis is 0.1 - 1 mic/mL. It is distributed well into bodily fluids. About 30%shows up in the urine as free drug and active metabolite while 60% shows up in thefeces as metabolite. The secretary is hounding me to finish the exam, so theanswer to 20 is a. Also, rifampin is 85% protien bound at physiological concen-trations. *a) 25 b) 50 c) 100 d) 150 e) 200

Answers:

Oral Dosing


A B IV

Tmax 1.27 1.7 0

K 0.25 0.25 0.25

ka 2.66 1.37 ---

AUC 53.9 57.7 39.8

Oral Dosing


Cpmax 10.6 9.9 10.02

PHARMACOKINETICS SECOND HOUR PRACTICE EXAM #2

(1) Succinctly define, stating rigorously the meaning of any symbols used and thedimensions of measurement:

a}Cpss b}feathering c}Wagner-Nelson method d}clearance e}f

(2) For each of the following pairs of variables (ordinate against abscissa), drawa graph illustrating the qualitative profile of their relationship. Where appropri-ate, indicate the nature of important slopes, intercepts, and values. Unless yourspecifically indicate on your plot that semi-log paper is being considered (write "S-L"), it will be assumed that rectilinear paper is being considered. Graphs are for adrug given by oral route where applicable.

Oral Dosing


a} total amount of drug collected minus the amount collected at the time in theurine vs time

b} Plasma concentration of a drug given by oral route vs time

c} Plasma concentration of metabolite of a drug given by IV bolus vs time

d} Steady state plasma concentration vs infusion rate

e} Steaty state plasma consentration vs clearance


SECTION I

(1) Succinctly define, stating rigorously the meaning of any symbols used and thedimensions of measurement:)

a}Cpss b}f c}Absolute Bioavailability d}Comparative Bioavailability

(2) Compare and contrast:a}Wagner-Nelson and feathering methods b} Treat-ment of plasma and urine data using Wagner-Nelson

(3) For each of the following pairs of variables (ordinate against abscissa), drawa graph illustrating the qualitative profile of their relationship. Where appropri-ate, indicate the nature of important slopes, intercepts, and values. Unless yourspecifically indicate on your plot that semi-log paper is being considered (write "S-L"), it will be assumed that rectilinear paper is being considered. Graphs are for adrug given by oral route where applicable.

dXu/dt vs t for a drug given orally.

Oral Dosing


dXmu/dt vs t for a drug given by IV bolus.

Steady state plasma concentration vs infusion rate

Steady state plasma concentration vs elimination rate constant


SECTION I

1. Succinctly define, stating rigorously the meaning of any symbols used and thedimensions of measurement:

a) clearance b)f c) absolute bioavailability d) comparative bioavailability e)AUC

2. By means of an annotated phase diagram explain how freeze-dried pharmaceuti-cal injectables are made.

3. For each of the following pairs of variables (ordinate against abscissa) draw agraph illustrating the qualitative profile of their relationship. Where appropriate,indicate the nature of important slopes, intercepts, and values. Unless you specifi-cally indicate on your plot that semi-log paper is being considered (write "SL"), itwill be assumed that rectilinear paper is being considered.

Pharmacological Response vs time

Peak time vs ka for oral dose

Fractional change in total body clearance vs. renal clearance

Oral Dosing


AUC vs ka

AUC vs ke


SECTION I


a) first pass effect b) f c) Intrinsic clearance

d) comparative bioavailability e) Extraction ratio

2. By means of an annotated phase diagram explain how a metastable polymorphcan be formed and how these polymorphs might effect the bioavailability of thedrug.

3. For each of the following pairs of variables (ordinate against abscissa) draw agraph illustrating the qualitative profile of their relationship. Where appropriate,indicate the nature of important slopes, intercepts, and values. Unless your specif-ically indicate on your plot that semi-log paper is being considered (write "S-L"),it will be assumed that rectilinear paper is being considered

fractional change in total body clearance vs plasma flow for drugs having a largeextraction ratio.

Peak time vs ka for oral dose

Fractional change in total body clearance vs. hepatic clearance.

AUC vs ka

Oral Dosing


AUC vs clearance


SECTION I


Henderson-Hasselbach relationship

Therapeutic alternatives

Therapeutic equivalents

comparative bioavailability

Extraction ratio

Briefly discuss generic substitution by the pharmacist. Include such topics as whenit might be admissable and the liabilities involved.

3. For each of the following pairs of variables (ordinate against abscissa) draw agraph illustrating the qualitative profile of their relationship. Where appropriate,indicate the nature of important slopes, intercepts, and values. Unless you specif-ically indicate on your plot that semi-log paper is being considered (write "S-L"),it will be assumed that rectilinear paper is being considered

a) fractional change in total body clearance vs fractional change in plasmaflow for drugs having a small extraction ratio.

Oral Dosing


b) Peak time vs dose for oral dose

c) Fractional change in total body clearance vs. fractional change in hepaticclearance for drugs having a large extration ratio.

d) Ratio of milk to blood for basic drugs vs pKa.

e) Ratio of milk to blood for acidic drugs vs pKa.


SECTION I


a) Bioequivalance

b) Intrinsic Clearance

c) first pass effect

d) Henderson - Hasselbach equation

e) f

2.Compare and contrast absolute and relative bioavailability.

3.For each of the following pairs of variables (ordinate against abscissa) draw agraph illustrating the qualitative profile of their relationship. Where appropriate,indicate the nature of important slopes, intercepts, and values. Unless you specif-ically indicate on your plot that semi-log paper is being considered (write "S-L"),it will be assumed that rectilinear paper is being considered

Oral Dosing


a) Cpmax vs f for a drug given orally.

b) Cpmax vs dose for a drug given orally.

c) Cpmax vs Vd for a drug given orally.

d) TBC vs Fi(H) for a drug with a high extraction ratio in the liver.

e) TBC vs Fr(H) for a drug with a high extraction ratio in the liver


SECTION I


a) Henderson-Hasselbach relationship

b) Therapeutic alternatives

c) Therapeutic equivalents

d) Comparative bioavailability

e) Extraction ratio

2. Briefly discuss generic substitution by the pharmacist. Include such topics aswhen it might be admissible and the liabilities involved.

3. For each of the following pairs of variables (ordinate against abscissa) draw agraph illustrating the qualitative profile of their relationship. Where appropriate,indicate the nature of important slopes, intercepts, and values. Unless you specifi-cally indicate on your plot that semi-log paper is being considered (write "SL"), itwill be assumed that rectilinear paper is being considered

a) fractional change in total body clearance vs fractional change in plasmaflow for drugs having a small extraction ratio.

Oral Dosing


b) Peak time vs dose for oral dose.

c) Fractional change in total body clearance vs. fractional change in intrinsichepatic clearance for drugs having a large extraction ratio.

d) Ratio of blood to milk concentrations for basic drugs vs pKa.

e) Ratio of blood to milk concentrations for acidic drugs vs pKa.

PHARMACOKINETICS SECOND HOUR PRACTICE EXAM # 10

SECTION I


a) Henderson-Hasselbach relationship

b) Therapeutic alternatives

c) Therapeutic equivalents

d) Comparative bioavailability

e) Absolute bioavailability

f) Bioequivalents

2. Compare and Contrast: Feathering and Wagner-Nelson method.

3. For each of the following pairs of variables (ordinate against abscissa), draw agraph illustrating the qualitative profile of their relationship. Where appropriate,indicate the nature of important slopes, intercepts, and values. Unless you indicateon your plot that semi-log paper is being considered (write SL), it will be assumedthat rectilinear paper is being considered. Graphs are for a drug given by an oraldelivery system where applicable.

a) Cpss vs. K

b) Cp vs. ka

Oral Dosing


c) Ratio of Milk to Blood for acidic drugs vs. pKa

Pharmacokinetics practice exam #11

Pharmaceutical alternatives may have different:

I. therapeutic moieties

II. dosage forms or strengths

III. salt or ester forms of the same therapeutic moiety

2) Pharmaceutical equivalents must have the same:

I. active ingredients and strength

II. dosage form and route of administration

III. rate and extent of absorption

3) Bioequivalent drug products must have the same:

I. active ingredients and strength

II. dosage form and route of administration

III. rate and extent of absorption

4) Therapeutic equivalents are:

Oral Dosing


I. pharmaceutical alternatives

II. pharmaceutical equivalents

III. bioequivalents

5) The Wagner-Nelson method

I. uses curve stripping or feathering techniques

II. can be used to find ku and km

III. uses AUC calculations

6) The Federal guidelines for for bioequivalence require that the following phar-macokinetic parameters be within + 20 % of

the innovator's product:

I. AUC, Peak time, Cpmax

II. Ka, Ke

III. Vd

7) The steady state plasma concentration of a drug given by intravenous infusion isdependent on:

I. length of time of of infusion

II. volume of distribution

III. elimination rate constant, K.

8) The peak time of a drug given by the oral route is dependent on:

Oral Dosing


I. the absorption rate constant

II. the metabolism rate constant

III. the excretion rate constant

9) The slope of the terminal portion of the graph of the metabolite of a drug which(the drug, not the metabolite) was given

by intravenous bolus injection could be:

I. - the elimination rate constant of the metabolite

II. - the elimination rate constant of the drug

III. - the absorption rate constant of the metabolite

10) Comparative bioavailability includes calculations of the ratio(s) of the fol-lowing pharmacokinetic parameters of two

oral products (generic / Innovator) normalized for dose :

I. AUC (0 to Inf)

II. Peak time

III. Cpmax

Pharmacokinetics practice second hour exam #12

Oral Dosing


Where the are only three foils (possible quesses), please use K type system:

(NOTE: if foils are equivalent, all must be selected)

A) I ONLY

B) III ONLY

C) I AND II ONLY

D) II AND III ONLY

E) I, II, AND III

1) Steady state plasma concentration obtained by continuous infusion is inverselyproportional to:

I Infusion rate

II elimination rate constant

III volume of distribution

2) Steady state plasma concentration obtained by continuous infusion is directlyproportional to:

I Infusion rate

II time

III volume of distribution

3) When calculating the AUC for an oral product using the trapezoidal rule, con-centrations necessary to calculate the

first trapezoid are:

Oral Dosing


I the intercept of the extrapolated line of the plasma vs. time profile.

II the concentration at time zero, Cp0

III the concentration at the first time point

4) When calculating the AUC for an IV product using the trapezoidal rule, con-centrations necessary to calculate the

first trapezoid are:

I the intercept of the extrapolated line of the plasma vs. time profile.

II the concentration at time zero, Cp0

III the concentration at the first time point

5) Absolute bioavailability is a calculation which

I must be between .80 and 1.20

II compares an oral product to an IV bolus dose.

III is the ratio of the normalized AUCs of the products tested.

6) Comparative bioavailability is a calculation which

I is the ratio of the normalized AUCs of the products tested.

II must be between .80 and 1.20

III compares an oral product to an IV bolus dose.

7) When plotting the Wagner-Nelson function vs. time, a plot which proceeds hor-izontally for a measurable time and then

declines:

Oral Dosing


I is because of poor data in the early part of the data set.

II only the declining portion should be used to calculate ka.

III is an indication of a delay in release of the drug from the delivery system, a lagtime.

8) When considering ion trapping, comparing a drug which forms sulfate saltsdistributing between mother's milk and

blood, the ratio of total drug in milk to total drug in blood (Rm/b) can be

I greater than one.

II one.

III less than one.

9) When considering ion trapping, comparing a drug which forms sodium saltsdistributing between mother's milk and

blood, the ratio of total drug in milk to total drug in blood (Rm/b) can be

I greater than one.

II one.

III less than one.

10) When using dry starch as a tablet disintegrating agent,

I tablet hardness is directly proportional to starch content.

II starch acts by allowing the water to wick into the tablet.

III a threshold minimum amount of starch is necessary before any disintegrationaction is apparent.

Oral Dosing


Cyclosporine A (Problem 8 - 6)

Quigano, R., et al., "Effect of atropine of gastrointestinal motility and the bioavailability of cyclosporine A in rats", Drug Metabo-lism and Disposition, Vol. 21, No. 1, (1993), p. 141 - 143.

In this study rats with an average weight of 300 g were given either an IV bolus dose of cyclosporine A (CyA)or an oral dose of CyA. Subsequently, doses of atropine were given; however, the data below is that which was gath-ered prior to atropine administration. A summary of the some of data obtained from this experiment is given below.

From the preceding data, please calculate the following:

1.

2. , the elimination rate constant

3.

Parameter IV Oral Solution Brand Tablet Generic Tablet Bioequivalence

Dose (mg/kg)

AUC

AUMC

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)

Relative Bioavailability

Generic Equivalent (Yes / No)

ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------

MRTiv

ke

t1 2⁄

Oral Dosing


4.

5.

6. The plasma concentration ( ) of cyclosporine A at 1 hour after the iv dose was given.

7. hour for the iv dose

8. , the absolute bioavailability of oral cyclosporine A.

9 .

10.

11. , the apparent absorption rate constant.

12. for the oral dose.

13. , the maximum concentration of the oral dosage form given as a single dose.

Cp0

Vd

Cp

AUC0 1–

f

MRToral

MAToral

ka

tpeak

Cpmax

Oral Dosing


Fosinopril (Problem 8 - 7)

Gehr, T., et al., "The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients", European Journal of Clin-ical Pharmacology, Vol. 45, No. 5, (1993), p. 431 - 436.

Fosinopril (MW 562.6) is a new Angiotension Converting Enzyme (ACE) Inhibitor used in the treatment ofhypertension. Following oral administration, fosinopril is rapidly and almost completely hydrolyzed to its pharmaco-logically active metabolite, fosinoprilate (MW 435.2). About 50% of the drug is excreted unchanged through the kid-neys. In this study, patients received either 7.5 mg of fosinoprilat administered intravenously or 10 mg of fosinopriladministered orally. A summary of the some of data obtained from this experiment is given below.


1.



Dose (mg/kg)

AUC

AUMC

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------

MRTiv

ke

Oral Dosing


3.

4.

5.

6. The plasma concentration ( ) of fosinopril at 1 hour after the iv dose was given.


8. , the absolute bioavailability of oral fosinopril.

9 .

10.




t1 2⁄

Cp0

Vd

Cp

AUC0 1–

f

MRToral

MAToral

ka

tpeak

Cpmax

Oral Dosing


Verapamil (Problem 8 - 8)

Rutledge, D., Pieper, J., and Mirvis, D., "Effects of chronic phenobarbital on verapamil disposition in humans", The Journal of Pharmacology and Experimental Therapeutics, Vol. 246, No. 1, (1988), p. 7 - 13.

This study focused on the effects of phenobarbital, a hepatic-enzyme inducer, on verapamil. Seven healthymale volunteers with an average weight of 78.8 kg participated in the study. The patients received either an single oralverapamil dose of 80 mg or a single intravenous verapamil dose of 0.15 mg/kg over 3 minutes. A summary of the someof data obtained from this experiment is given below.


1.


3.


Dose (mg/kg)

AUC

AUMC

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------

MRTiv

ke

t1 2⁄

Oral Dosing


4.

5.

6. The plasma concentration ( ) of verapamil at 1 hour after the iv dose was given.


8. , the absolute bioavailability of oral verapamil.

Cp0

Vd

Cp

AUC0 1–

f

Oral Dosing


Zidovudine (Problem 8 - 9)

Trang, J., et al., "Zidovudine bioavailability and linear pharmacokinetics in female B6C3F1 mice", Drug Metabolism and Disposi-tion Vol, 21 (1993), p.189 - 193.

Zidovudine (AZT) is a potent inhibitor of HIV-1 during viral replication. It has been approved for the treat-ment of AIDS. In this study a 30 mg/kg dose of AZT was given to mice either iv or orally. :A summary of the someof data obtained from this experiment is given below.


1.


3.

4.


Dose (mg/kg)

AUC

AUMC

MRT (hr)

MAT (hr)

ke (hr-1)

ka (hr-1)

Cp0

Vd (L)

Cp at 1 hour

f

Cpmax

Tmax (hr)



ugmL-------- hr⋅

ugmL-------- hr

2⋅

ugmL--------

ugmL--------

ugmL--------

MRTiv

ke

t1 2⁄

Cp0

Oral Dosing


5.

6. The plasma concentration ( ) of zidovudine at 1 hour after the iv dose was given.


8. , the absolute bioavailability of oral zidovudine.

9 .

10.




Vd

Cp

AUC0 1–

f

MRToral

MAToral

ka

tpeak

Cpmax