CHAPTER 7

Oral Dosing

Author: Michael Makoid and John Cobby Reviewer: 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 ( V d , K, k m , k r , k a , AUC , Clearance, MRT, MAT) available from oral data. Given patient drug concentration and/or amount vs. Time profiles, the student will calculate (III) the K from the terminal portion of the curve. Given patient drug concentration and/or amount vs. Time profiles, the student will calculate (III) the k a from either the curve stripping Moment techniques. 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. 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. 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 ( Cp ) max ). Given patient drug concentration and/or amount vs. Time profiles, the student will evaluate (IV) bioequivalence data. 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.

2. 3. 4.

5.

6.

7. 8.

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7-1

Oral Dosing

9.

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

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Oral Dosing

7.1 Oral dosing
7.1.1 VALID EQUATIONS: ( ORAL DOSING, PLASMA)
ka –k t – Kt C p = fD ⋅ -------------- ⋅ ( e – e a ) ----Vd k a – K AUC ( oral ) ⁄ Dose ( oral ) f = -------------------------------------------------------------AUC ( iv ) ⁄ Dose ( iv ) AUC ( generic ) ⁄ Dose ( generic ) CB = ------------------------------------------------------------------------------------AUC ( inovator ) ⁄ Dose ( inovator ) ln ( k a ⁄ K ) t p = ----------------------( ka – K ) Xa ----- = K ⋅ AUC ∞ – ( C p + K ⋅ AUC t ) v where
CB
(EQ 5-18)

(EQ 5-19)

(EQ 5-20)

(EQ 5-21)

(EQ 5-22)

= the comparative bioavailability

f = the absolute bioavailabilty; the fraction of dose which ultimately reaches systemic circulation (which is made up of the fraction of the dose which is absorbed times the fraction which gets past the liver (first pass effect)) ka

= absorption rate constant.

7.1.2

UTILIZATION

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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 an AUC of 11 mic/mL*hr. The following blood level profile has been reported for two brands of ampicillin which were given as 500 mg oral capsules.

TABLE 4-7

Time (hr) 0.5 1.0 1.5 2.0 3.0 4.0 6.0

µg MEAN SERUM LEVEL ------mL LEDERLE 0.37 1.97 2.83 3.15 2.73 1.86 0.43 BRISTOL 0.38 1.91 2.49 3.11 2.79 1.95 0.49

Find the following:. a. b. c. d. e. f. g. h. i j. k. l. k for both products. k a for both products. k u for both products. AUC for both products. f for both products. t max for both products. Cl Vd Cp 0 for a 250 mg IV dose. Cp max Are these two products bioequivalent? Why or why not? What infusion rate would be necessary to maintain a serum 7-4

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Oral Dosing

plasma concentration of 2mcg/mL

The data was plotted as above with the best fit line drawn. From the graph the following parameters were derived:
TABLE 4-8 Comparison

of Ampicillin
Lederle Bristol 0.635 0.831 1.8 2.9 11.6 0.97 1.03 0.98 Ratio (L/B)

K ( hr ) K a ( hr ) T max ( hr ) ( C p ) max ( µg ⁄ mL ) AUC (trapaziodal)
–1

–1

0.688 0.858 1.74 3 11.4

2) In a clinical study (DiSanto & DeSante, JPS 64:100,1975) prednisone was administered to 22 adult healthy volunteres (average weight 64.5 kg) either as one 50 mg tablet (product A) or as ten 5 mg tablets (product B). The following data was observed: Time (hours) A
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Concentration (mic/100ml plasma) B 7-5

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0.5 1 2 3 4 6 8 12 24

40.8 70.0 79.5 80.7 68.6 49.4 35.0 15.3 2.1

57.3 77.1 82.3 69.4 60.6 48.0 33.7 17.4 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:

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Oral Dosing

Product A Ka (hr^-1) Tmax (hr) Cmax (mcg/100mL)83.2 AUC (trapazoidal)676.52 1.19 2 82.8 688.81

Product B 1.8 1.52

Ratio (A/B)

1.31 1.00 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 healthy volunteers in a four way crossover design of four dosage forms containing 300 mg of cimetadine. The following data was obtained:

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Oral Dosing

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

B 5.4

C

D

% recovered in urine intact77.177.147.149.0 Peak serum conc.(mic/ml)------ 1.53 1.44 Onset (hr) Duration (hr) Time to peak (hr)0 0 4.5 4.0 1.0 0.34 4.2 2.0 0.65 4.4

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) 1 2 4

(ug/ml) 1.79 1.36 0.78 6 12

time(hrs) 0.45 0.08

(ug/ml)

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?

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Oral Dosing

f} What infusion rate would you suggest to maintain a plasma concentration of 0.75 mic/ml ? g} How long would it take that infusion rate to attain a therapeutic plasma concentration of 0.5 mic/ml ? Answer:

IV Bolus Parameters: Cp max2.4 mic/mL AUC 8.5 K 0.283 hr^-1

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Oral Dosing

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

b} What is the absolute bioavailability (f) of the liquid. 5/2/8.5 = 0.61

c} How does that correlate with % recovered intact in the urine? Very well. Only 61% (f) of liquid gets in and you would expect only 77% of that to show 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 of 0.75 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 concentration 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 4) LYSERGIC ACID DIETHYLAMIDE (LSD) was given to human volunteers at the dose of 150 mic orally. (Impregnated blotter dosage form.) The following data was obtained:

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Oral Dosing

Time 0.25 0.5 0.75 1.0 1.5

Cp (ng/ml) 1.75 2.9 3.7 4.2 4.6 2.0 3.0 4.0 6.0 8.0

Time 4.6 4.1 3.3 2.1 1.4

Cp (ng/ml)

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 standard tasks was also monitored. (100% control means no drug interference.) The following data was obtained: Cp (ng/ml) 5.5 4.1 2.9 33 40 52 % Control 1.5 1.1 Cp (ng/ml) 65 80 % Control

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

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Oral Dosing

Evaluation of the graph of Concentration vs. time yields:

Cpmax T max

4.63 ng/mL 1.7 hr

AUC (trap)30.07 K 0.225 hr^-1

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Oral Dosing

m (-K) Ka

-0.225 hr^-1 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 between 500 mg dose of cloxacillin made by Bristol (Tegopen@) and a generic product which you might want to put in your store. Time (Conc. mic/ml) Time (Conc. mic/ml) TEGOPEN GENERIC

TEGOPEN GENERIC

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Oral Dosing

0.25 0.5 0.75 1 1.25

.41 8.56 11.97 11.28 9.57

0.1 6.39 11.44 11.42 9.64

1.5 2 3 4

6.93 4.95 2.19 1.48

7.75 5.16 2.29 1.30

Calculate the comparative bioavailability. Would you consider these products bioequivalent? Why/Why not? Answer:

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Oral Dosing

Evaluation of the above graphs yields: Tegopen GenericRatio (G/T)

Cpmax (mic/mL)10.8 T max (hr) AUC (trap) K (hr^-1) ka (hr^-1) 0.74 21.7 0.72 4.3

9.94 0.89 21.06 0.8 2.69

0.92 1.20 0.97

Actual evaluation of ka and peak time is dificult because of the pucity of data at early time points however all relavent parameters meet guidlines. 7. The F.D.A. reported the following data submitted to be consideration regarding the equivalence of Mylan Pharmaceuticals' Tetracycline with that of Lederle and an intervenous bolus dose. (Dose 250 mg). Time(hrs) Conc.(mcg/ml) Time(hrs) Lederle Mylan I.V. 0.5 1 1.5 2 0.55 0.20 5.2 1.80 1.35 4.8 2.11 1.75 4.4 2.35 2.10 4.0 4 6 9 12 Conc.(mcg/ml)

Lederle Mylan I.V. 2.70 2.60 2.9 2.20 1.80 2.1 1.35 1.25 1.26 0.83 0.74 0.76

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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 and enamel of developing teeth causing hypoplasia and permanent discoloration of teeth. 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 he eats 2 oz of milk every 2 hours. Mom's average plasma concentration is maintained at 3 mic/ml by taking 250 qid. pH of the milk is 6.1, pH of blood is 7.4) Answer:

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Oral Dosing

Pharmacokinetic parameters: Lederle Cpmax (mic/mL)2.75 2.42 Tmax (hr) AUC k (hr^-1) Ka (hr^-1) 0.165 0.684 3.04 26.4 0.161 0.729 3.08 23.3 0.167 Mylan 5.65 0 31.4 IV

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

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

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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 getting more than mom. Fifty miligrams of ketameperidine was given by IV bolus. The following urinary profile was obtained for the only metabolite N-methyl-ketameperidine:

Collection period (hr) 0.0 - 0.5 0.5 - 1.5 1.5 - 2.5 2.5 - 3.5 3.5 - 5.0

Mean urinary excretion rate (mg/hr) 2.26 5.83 5.43 4.60 2.36

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Oral Dosing

5.0 - 7.0 7.0 -10.0 10.0 -18.0

1.47 0.96 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 question. The terminal slope is assumed to be K. The AUC will yield the amount of ketameperidine 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

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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 inactive metabolites. THEOPHYLLINE has a therapeutic range between 20 and 10 mg/l. AUC FROM 0 to infinity for THEOPHYLLINE (given as 400 mg AMINPHYLLINE) is 120 mg/l x hr. The average plasma concentration of THEOPHYLLINE given as 400 mg of AMINOPHYLLINE is as follows: time (hrs) 0.5 1.0 2.0 3.0 conc. time (mg/L) (hrs) 7.24 9.56 4.0 6.0 conc. (mg/L) 8.06 6.89 5.57 4.53

10.00 8.0 8.84 10.0

Find f, K, ka, Vd,total body clearance. Find the infusion rate necessary to maintain a plasma concentration of 15 mg/l.

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Oral Dosing

Answer: AUC (mg/L)*hr117.8 K (hr^-1) ka (hr^-1) 0.096 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

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Oral Dosing

Infusion rate = Q = Cpss * TBC = 15 mg/L * 2.83 L/hr = 42.45 mg/hr Theophylline = 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 (hrs) 0.5 1.0 1.5 2.0

conc. time (mg/L) (hrs) 0.05 0.21 0.27 0.31 3.0 4.5 6.0 8.0

conc. (mg/L) 0.31 0.23 0.18 0.12

a Find K, ka, Cmax,

Answer:

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Oral Dosing

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

The parameters obtained from each fit are:

WithoutWith

Cpmax (mg/L)0.22 Tmax (hr) 3.45 2.26

0.31 2.28

AUC (mg/L*hr)2.2 K (hr^-1) ka (hr^-1) t lag (hr) 0.216 0.380 0.0

0.201 1.10 0.393

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Oral Dosing

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

Wilkenstein et al.(Gastroenterology 74:360,1978) tested 12 normal healthy volunteers in a four way crossover design of four dosage forms containing 300 mg of cimetadine. The following data was obtained: A B C D AUC(mic/ml x hr) ----54.9 1.53 5.2 55.8 1.44 0.34 4.6 1.0 4.2 0.65 4.4 2.0 5.4

recovered in urine intact77.177.1 Peak serum conc.(mic/ml)--- --Onset (hr) Duration (hr) Time to peak (hr) 0 0 4.5

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) 1 2 4 6 12 a} find K, Cp0. Both can be found from the graph. K = .283/hr Cp0 = 2.36 mic/ml conc.(ug/ml) 1.79 1.36 0.78 0.45 0.08

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Oral Dosing

b} What is the absolute bioavailability (f) of the liquid. 5.2/8.5 = 0.61

c} How does that correlate with % recovered intact in the urine? Very well. Only 61% (f) of liquid gets in and you would expect only 77% of that to 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 of 0.75 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 concentration 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 their Quinidine Sulfate tablets (Dose 200 mg). It is compared against the reference standard by Ely Lilly and company at the same dose.

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Oral Dosing

Time (hours)Concentration (mcg/ml) Roxane 1 2 3 4 6 8 12 .42 .73 .71 .61 .45 .32 .20 Lilly .58 .77 .74 .66 .52 .34 .22

a) Calculate the comparative bioavailability. b) Would you consider Roxane Quinidine Sulfate to be bioequivalent to the Lilly product ?

Answers

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Oral Dosing

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Oral Dosing

Roxane labsEli Lilly w/o w w/o w Rw/o(R/L)Rw(R/L) 0.97 0.91 1.15 0.98

Cpmax (mcg/mL)0.650.740.740.76 0.88 AUC (mcg/mL*hr)6.086.236.756.84 0.90 Tmax (hr) T lag (hr) 2.69 0.0 2.05 0.70 2.33 0.0 2.10 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 1 1.5 2 3 4 5 6 7 ---29 24 18 15 11 9 50 77 100 100 90 78 59 45 32

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Oral Dosing

a) find ka b) Calculate the absolute bioavailability of propranolol. c) Calculate TBC

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Oral Dosing

IV data

Oral Data w/o w

AUC (ng/mL*hr)201.3562.8 540 Cpmax (ng/mL) 47.7 97.8 Tmax (hr) K (hr^-1) ka (hr^-1) T lag 0 0.239 --99.7 2.0 2.1

0.324 0.421 0.715 0.548 0.0 0.02

Absolute bioabailability = (AUCoral/DOSEoral)/(AUCiv/DOSEiv) = (562.8/80) (540 / 80) /(201.3/10) = 0.35 or using lag time data /(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.

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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. Because of the decrease in TBC, we can see that the drug is staying the body much longer than normal, therefore the dosage regimen should be decreased. Chlorthalidone is used to treat high blood pressure. The following information is offered regarding a generic and a brand name chlorthalidone 50 mg tablet: Time Conc. (mcg/ml)

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Oral Dosing

(hours) .5 1 2 3 4 6 8 12 24 48 72 96 120

Hygroton@Generic 0.14 0.51 1.23 1.94 2.20 2.64 2.86 3.43 3.22 2.45 1.53 1.20 0.76 0.15 0.64 1.67 2.48 2.91 3.49 3.52 3.82 3.38 2.74 1.91 1.40 0.77

Pharmacokinetic parameters Cpmax (mg) 3.73 4.62

Time to peak (hr) 13.810.8 AUC (0 to Inf)293 Xu inf (mg)18.3 Ka (hr^-1)0.168 Ke (hr^-1)0.019 336 22.1 0.253 0.019

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Oral Dosing

Average mean83.1 blood presure

84.5

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 patient regarding 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 of the 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 the treatment of generalized anxiety disorder at a mean dose of approximately 20 mg/ day orally in divided doses. Buspirone is metabolized almost entirely. Less than 0.1% is found intact in the urine. The following data has been presented by Gammans (Am J Med:80(supp 3b),41-51;1986): Time (hours)Concentration (ng/ml) (hours) 1 mg I.V.20 mg oral

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0.25 0.50 1.0 2 3 4 6

-4.33 3.75 2.80 2.10 1.57 0.8

1.07 1.76 2.45 2.51 2.05 1.60 0.91

a) find ka b) Find Oral Peak Time and Oral Cmax. c) Calculate the absolute bioavailability of buspirone.

answer:

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Oral Dosing

IV Cpmax (ng/mL) 5.0 2.6 AUC (0 to inf)17.4 Tmax (hr) K (hr^-1) ka (hr^-1) 0 13.9 1.5

Oral

0.290 0.289 1.3

Absolute bioavailability, f, = (AUCoral/DOSEoral)/(AUCiv/DOSEiv) = ( 13.9 / 20) = 0.04 Valproate is a carboxylic acid anticonvulsant. Its activity may be related, at least in part, to increase concentrations of the neurotransmitter inhibitor gamma aminobutyric acid in the brain. It is used alone or in combination with other anticonvulsants. in the prophylactic management of petit mal. It appears to be almost entirely cleared by liver function with negligible amounts excreted into the urine unchanged. It comes as soft gelatin capsules of 250 mg and enteric coated tablets 250 and 500 mg as well as oral syrup of 250 mg / 5 cc. Two different formulations of Valproate (250 mg) were prepared by Abbott and compared. The data is as follows: /( 17.4/ 1 )

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Time(Hr.)Formulation BFormulation A 0.5 1.0 1.5 2.0 2.5 3.0 4.0 6.0 8.0 12.0 18.0 24.0 3.4 6.0 7.9 9.3 10.3 10.9 11.6 11.4 10.5 8.3 5.7 3.8 AUC = 287 mg/L * hr Ka = 0.7 hr^-1 Ke = 0.065 hr^-1

1) find ka for formulation B. 2) Five hundred mg of valproate was administered by IV bolus. The AUC for that route was 574 mg/L * hr. Calculate f for formulation A. Calculate Cp0 for the IV dose. 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 ? Prepare a short statement in which you would substantiate that stand that you might

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need to respond to another health professional who asked you to stock that formulation 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 K = 0.493 hr^-1 = 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

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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 generic Procainamide HCl. (Dose 250mg). Procainamide is a base (pka =9.1). As the hydrochloride salt it is 87% Procainamide.

Time (hrs)Conc.(mcg/ml) Procainamide Base Lederle 0.33 0.5 0.66 1 1.33 2 3 4 6 8 12 0.68 0.82 1.17 1.23 1.31 1.39 0.93 0.74 0.51 0.32 0.11 Squibb 0.26 0.67 0.93 1.12 1.19 1.12 0.96 0.74 0.51 0.30 0.09 1.45 1.35 1.18 0.95 0.77 0.51 0.33 0.14 I.V.

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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 short consult 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 average plasma concentration is maintained at 4 mic/ml from a 1 g dose ever 6 hours. pH of the milk is 6.3, pH of blood is 7.4) Procainamide is cleared about 60% by liver and 40% by kidney function. 20 % of cardiac output (70 ml/min/kg) goes to liver, 25% goes to the kidney. Mom's weight is 130 lb. Assuming her plasma vs time profile to be similar to the Lederle product (i.e. pharmacokinetic parameters obtained from this information can be used): 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 hepatitis which effect liver function (FI = 0.4). Prepare a short consult for her physician as to whether you would recommend a change in therapy. d) Calculate the effect on her total body clearance stenosis of the liver (FR = 0.4). Prepare a short consult for her physician as to whether you would recommend a change in therapy. Answers:

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IV

LederleSquibb R(L/S) 1.09 1.25 1.45 1.02 0.99

AUC (0 to inf)8.577.46.8 Cpmax Tmax K ka t lag 1.8 0 1.28 1.43

0.212 0.247 0.256 --0 1.51 0 1.93 0.24

Absolute bioavailability, f,=(AUCoral/DOSEoral)/(AUCiv/DOSEiv) = 7.4 / 8.57

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= 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 inhibits potential-dependent channels not receptor-operated channels, preventing calcium influx of cardiac and vascular smooth muscle (coronary, cerebral). Calcium channel blockers reduce myocardial contractility and A-V node conduction by reducing the slow inward calcium current. They are indicated in angina, cardiac dysrhythmias, and hypertension among others. Nifedipine appears to be metabolized entirely into an inactive metabolite, an acid and subsequently further metabolized to a lactone. Both the acid and the lactone are excreted into the urine and the feces.

Echizen and Eichelbaum (Clin Pkin 1986; 11:425-49) and Kleinbloesem et al (Clin Pcol Therap 1986; 40: 21-8) Reviewed the pharmacokinetics of Nifedipine. While the drug is not routinely given by IV bolus and does not strictly conform to a one compartment model, lets treat the data as if those problems can be ignored. The following data is offered for evaluation: 25mg IV 10 mg oral tablet Formula AFormula B Time Cp Cp Cp

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(hr.) 0.5 1 1.5 2 3 4 6 8 12

(mic/l)

(mic/l) 29.3 42.1 45.7

(mic/l) 33.1 43.7 43.7 39.8 25.5 20.7 9.9 4.7 1.0

139

44.4 36.2

65.6 31.1 14.6

27 13.6 6.5 1.5

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 you argument) e) Calculate the absolute bioavailability of product A. f} What infusion rate would you suggest to maintain a plasma concentration of 30 mic/L ? Answers:

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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.

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Oral Dosing

Absolute bioavailability, f,=(AUCoral/DOSEoral)/(AUCiv/DOSEiv) =(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 and enamel of developing teeth causing hypoplasia and permanent discoloration of teeth. Would you recommend tetracycline for a lactating mother ? 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 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's milk.

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

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

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Oral Dosing

mic/ml for nursing 120 lb mother, would her 9 lb infant be getting a comparable mg per kg daily dose if he consumes 2 oz of his mothers milk every 2 hours. Prepare a short consult for her physician in which you might (or might not) recommend the patient stop breast feeding while she is on this medication. Include appropriate 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 should discontinue breast feeding while taking Oxazepam. Bioequivalence studies are sometimes done within the same company to check if the 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 to one 10 mg tablet). While not strictly kosher (products are not pharmaceutical equivalents because of different strengths), it is done. Here is the results of such a study in which Zomax 100 and 200 mg tablets were compared. (Yes, I know that Zomax 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 (hr) 0.25 0.5 0.75 1 (mg/L) (0->t) 1.41 1.98 2.15 2.12 0.18 0.60 1.12 1.65 Conc AUC (mg/L) (0->t) 4.03 5.13 5.18 4.89 0.50 1.65 2.94 4.20 1.14 Conc. (mg/L)

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2 3 4 6 8

1.56 1.05

3.49 4.80

3.37 2.26 1.51 0.68

8.33 11.14 13.03 15.22

0.764 0.512 0.343 0.154 0.069

0.707 5.67 0.318 6.70 0.143 7.16

0.306 16.20

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

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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 (7.48/100)/(4.25/50) = 0.88 D) 1.14 E) 1.19

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 (16.9/200)/(4.25/50) = 1 D) 1.14 E) 1.19

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

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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 for dose) (consider all ratios to be the 100 mg / 200 mg parameter normalized as to dose 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

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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 concentration 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 infusion 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 following 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 the blood ? A) 0.05 B) 0.5 C) 1 D) 2 *E) 20

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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 consumes 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 is 0.12. 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 the mother's dose is 1.2. E) Not my job. I only give what the doctor orders. Answers:

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Oral Dosing

IV

Tablet Tablet

50 mg 100 mg200 mgR(100/200) AUC(0 to inf)4.257.4816.9 Cpmax Tmax K ka 1.7 0 0.4 --2.15 0.82 0.4 2.76 0.89 5.23 0.64 -.4 4.01 0.82 1.28

Tmax ratio is ouside guidelines.

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Oral Dosing

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

Rifampin (unionized free base pKa 7.9) is a drug used to treat TB. The following data 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 Time (hours) 0.5 1 1.5 2 2.5 3 4 6 8 10 12 5.3 10.3 10.2 9.4 8.9 7.5 5.9 3.6 2.2 1.3 0.8 4.8 8.6 9.8 9.8 9.2 8.4 6.7 4.1 2.5 1.5 0.92 4.7 3.7 2.2 1.3 0.8 0.5 6.1 7.8 1.2 4.55 9.15 14.05 18.8 B C B

AUC(0->inf)53.957.7

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(mic/mL*hr) Lag time (min)18.610.5 Cp max10.6 Ka (hr^-1)2.66 9.9

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)? d) 33.3 e) 26.7

a) 60

b) 51.3 *c) 40

Vd = D/Cp0 = 400mg/(9.95mg/L) = 40.2 L

3) What is the half life for rifampin (hr)? 1.5

*a) 2.8

b) 2.3

c) 2.0

d) 1.75 e)

t1/2 = .693/0.25 = 2.77

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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). 8.9 e) 17.8

a) 1.95 *b) 3.9 c) 7.8 b)

6) Calculate the AUC (12hr->inf.) for C (mic/mL*hr). d) 1.25 e) 1.11

*a) 2

b) 1.67 c) 1.43

0.5/0.25 = 2 7) Calculate the AUC (0->inf) for C (mic/mL*hr). 40 e) 60 a) 16 b) 26.85 c) 35 *d)

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

a) 0.70 *b)

(57.7/600)/(39.8/400) = 0.966 9) Calulate the comparative bioavailability for the generic product. 0.95 c) 1 *d) 1.05 e) 1.43 a) 0.70 b)

(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

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11) Calculate the peak time for the generic product (min). 91 e) 105

a) 37 b) 67 c) 86 d)

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). 86 d) 95 e) 105 a) 37 *b) 59 c)

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 requirements.

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)

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= 20

15) The average plasma concentration for the mother (110#) is 2.5 mg/L from a 600 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 50 mg/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 daily dose (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/day basis. 17) While Rifampin is not administered by IV infusion, what would be the infusion 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

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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 loading dose 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 infusion rate necessary to obtain a plasma concentration of 2.5 mg/L in about 2.5 to 3 hours (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 derived from 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 the feces as metabolite. The secretary is hounding me to finish the exam, so the answer to 20 is a. Also, rifampin is 85% protien bound at physiological concentrations. *a) 25 b) 50 c) 100 d) 150 e) 200 Answers:

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Oral Dosing

A Tmax K ka AUC 1.27 0.25 2.66 53.9

B 1.7 0.25 1.37 57.7

IV 0 0.25 --39.8

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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 the dimensions 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), draw a graph illustrating the qualitative profile of their relationship. Where appropriate, indicate the nature of important slopes, intercepts, and values. Unless your specifically indicate on your plot that semi-log paper is being considered (write "SL"), it will be assumed that rectilinear paper is being considered. Graphs are for a drug given by oral route where applicable.

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

PHARMACOKINETICS SECOND HOUR PRACTICE EXAM #3

SECTION I

(1) Succinctly define, stating rigorously the meaning of any symbols used and the dimensions of measurement:) a}Cpss b}f c}Absolute Bioavailability d}Comparative Bioavailability

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

b} Treat-

(3) For each of the following pairs of variables (ordinate against abscissa), draw a graph illustrating the qualitative profile of their relationship. Where appropriate, indicate the nature of important slopes, intercepts, and values. Unless your specifically indicate on your plot that semi-log paper is being considered (write "SL"), it will be assumed that rectilinear paper is being considered. Graphs are for a drug given by oral route where applicable. dXu/dt vs t for a drug given orally.

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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

PHARMACOKINETICS SECOND HOUR PRACTICE EXAM #4

SECTION I

1. Succinctly define, stating rigorously the meaning of any symbols used and the dimensions 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 pharmaceutical injectables are made.

3. For each of the following pairs of variables (ordinate against abscissa) draw a graph illustrating the qualitative profile of their relationship. Where appropriate, indicate the nature of important slopes, intercepts, and values. Unless you specifically indicate on your plot that semi-log paper is being considered (write "SL"), it will 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

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Oral Dosing

AUC vs ka AUC vs ke

PHARMACOKINETICS SECOND HOUR PRACTICE EXAM #5

SECTION I 1. Succinctly define, stating rigorously the meaning of any symbols used and the dimensions of measurement: 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 polymorph can be formed and how these polymorphs might effect the bioavailability of the drug.

3. For each of the following pairs of variables (ordinate against abscissa) draw a graph illustrating the qualitative profile of their relationship. Where appropriate, indicate the nature of important slopes, intercepts, and values. Unless your specifically 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 large extraction ratio. Peak time vs ka for oral dose Fractional change in total body clearance vs. hepatic clearance. AUC vs ka

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Oral Dosing

AUC vs clearance

PHARMACOKINETICS SECOND HOUR PRACTICE EXAM #6

SECTION I 1. Succinctly define, stating rigorously the meaning of any symbols used and the dimensions of measurement: Henderson-Hasselbach relationship Therapeutic alternatives Therapeutic equivalents comparative bioavailability Extraction ratio

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

3. For each of the following pairs of variables (ordinate against abscissa) draw a graph illustrating the qualitative profile of their relationship. Where appropriate, indicate the nature of important slopes, intercepts, and values. Unless you specifically 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 plasma flow for drugs having a small extraction ratio.

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Oral Dosing

b)

Peak time vs dose for oral dose

c) Fractional change in total body clearance vs. fractional change in hepatic clearance for drugs having a large extration ratio. d) e) Ratio of milk to blood for basic drugs vs pKa. Ratio of milk to blood for acidic drugs vs pKa.

PHARMACOKINETICS SECOND HOUR PRACTICE EXAM #7

SECTION I 1. Succinctly define, stating rigorously the meaning of any symbols used and the dimensions of measurement: 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 a graph illustrating the qualitative profile of their relationship. Where appropriate, indicate the nature of important slopes, intercepts, and values. Unless you specifically indicate on your plot that semi-log paper is being considered (write "S-L"), it will be assumed that rectilinear paper is being considered

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Oral Dosing

a) b) c) d) e)

Cpmax vs f for a drug given orally. Cpmax vs dose for a drug given orally. Cpmax vs Vd for a drug given orally. TBC vs Fi(H) for a drug with a high extraction ratio in the liver. TBC vs Fr(H) for a drug with a high extraction ratio in the liver

PHARMACOKINETICS SECOND HOUR PRACTICE EXAM #9 SECTION I 1. Succinctly define, stating rigorously the meaning of any symbols used and the dimensions of measurement: 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 as when it might be admissible and the liabilities involved.

3. For each of the following pairs of variables (ordinate against abscissa) draw a graph illustrating the qualitative profile of their relationship. Where appropriate, indicate the nature of important slopes, intercepts, and values. Unless you specifically indicate on your plot that semi-log paper is being considered (write "SL"), it will be assumed that rectilinear paper is being considered a) fractional change in total body clearance vs fractional change in plasma flow for drugs having a small extraction ratio.

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Oral Dosing

b)

Peak time vs dose for oral dose.

c) Fractional change in total body clearance vs. fractional change in intrinsic hepatic clearance for drugs having a large extraction ratio. d) e) Ratio of blood to milk concentrations for basic drugs vs pKa. Ratio of blood to milk concentrations for acidic drugs vs pKa.

PHARMACOKINETICS SECOND HOUR PRACTICE EXAM # 10 SECTION I 1. Succinctly define, stating rigorously the meaning of any symbols used and the dimensions of measurement: 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 a graph illustrating the qualitative profile of their relationship. Where appropriate, indicate the nature of important slopes, intercepts, and values. Unless you indicate on your plot that semi-log paper is being considered (write SL), it will be assumed that rectilinear paper is being considered. Graphs are for a drug given by an oral delivery system where applicable. a) b) Cpss vs. K Cp vs. ka

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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:

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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 pharmacokinetic 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 is dependent 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:

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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 following 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

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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 inversely proportional to: I Infusion rate II elimination rate constant III volume of distribution

2) Steady state plasma concentration obtained by continuous infusion is directly proportional to: I Infusion rate II time III volume of distribution

3) When calculating the AUC for an oral product using the trapezoidal rule, concentrations necessary to calculate the first trapezoid are:

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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, concentrations 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 horizontally for a measurable time and then declines:

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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 lag time.

8) When considering ion trapping, comparing a drug which forms sulfate salts distributing 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 salts distributing 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 disintegration action is apparent.

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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 Metabolism 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 gathered 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:

Parameter Dose (mg/kg) ug AUC  ------- ⋅ hr  mL 
2 ug AUMC  ------- ⋅ hr   mL 

IV

Oral Solution

Brand Tablet

Generic Tablet

Bioequivalence

MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ug Cp0  -------  mL Vd (L) ug Cp at 1 hour  -------  mL f ug Cpmax  -------  mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)

1. 2. 3.

MRT iv k e , the elimination rate constant t1 ⁄ 2

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Oral Dosing

4. 5. 6. 7. 8. 9 10. 11. 12. 13.

Cp 0 Vd
The plasma concentration ( Cp ) of cyclosporine A at 1 hour after the iv dose was given.

AUC 0 – 1 hour for the iv dose f , the absolute bioavailability of oral cyclosporine A. MRT oral . MAT oral k a , the apparent absorption rate constant. t peak for the oral dose. Cp max , the maximum concentration of the oral dosage form given as a single dose.

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7-74

Oral Dosing

Fosinopril

(Problem 8 - 7)

Gehr, T., et al., "The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients", European Journal of Clinical 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 of hypertension. Following oral administration, fosinopril is rapidly and almost completely hydrolyzed to its pharmacologically active metabolite, fosinoprilate (MW 435.2). About 50% of the drug is excreted unchanged through the kidneys. In this study, patients received either 7.5 mg of fosinoprilat administered intravenously or 10 mg of fosinopril administered orally. A summary of the some of data obtained from this experiment is given below.

Parameter Dose (mg/kg) ug AUC  ------- ⋅ hr  mL 
2 ug AUMC  ------- ⋅ hr   mL 

IV

Oral Solution

Brand Tablet

Generic Tablet

Bioequivalence

MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ug Cp0  -------  mL Vd (L) ug Cp at 1 hour  -------  mL f ug Cpmax  -------  mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)

From the preceding data, please calculate the following: 1. 2.

MRT iv k e , the elimination rate constant

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7-75

Oral Dosing

3. 4. 5. 6. 7. 8. 9 10. 11. 12. 13.

t1 ⁄ 2 Cp 0 Vd
The plasma concentration ( Cp ) of fosinopril at 1 hour after the iv dose was given.

AUC 0 – 1 hour for the iv dose f , the absolute bioavailability of oral fosinopril. MRT oral . MAT oral k a , the apparent absorption rate constant. t peak for the oral dose. Cp max , the maximum concentration of the oral dosage form given as a single dose.

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7-76

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 healthy male volunteers with an average weight of 78.8 kg participated in the study. The patients received either an single oral verapamil dose of 80 mg or a single intravenous verapamil dose of 0.15 mg/kg over 3 minutes. A summary of the some of data obtained from this experiment is given below.

From the preceding data, please calculate the following:

Parameter Dose (mg/kg) ug AUC  ------- ⋅ hr  mL 
2 ug AUMC  ------- ⋅ hr   mL 

IV

Oral Solution

Brand Tablet

Generic Tablet

Bioequivalence

MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ug Cp0  -------  mL Vd (L) ug Cp at 1 hour  -------  mL f ug Cpmax  -------  mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)

1. 2. 3.

MRT iv k e , the elimination rate constant t1 ⁄ 2
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Basic Pharmacokinetics
Copyright © 1996-1999 Michael C. Makoid All Rights Reserved

7-77

Oral Dosing

4. 5. 6. 7. 8.

Cp 0 Vd
The plasma concentration ( Cp ) of verapamil at 1 hour after the iv dose was given.

AUC 0 – 1 hour for the iv dose f , the absolute bioavailability of oral verapamil.

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7-78

Oral Dosing

Zidovudine

(Problem 8 - 9)

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

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

Parameter Dose (mg/kg) ug AUC  ------- ⋅ hr  mL 
2 ug AUMC  ------- ⋅ hr   mL 

IV

Oral Solution

Brand Tablet

Generic Tablet

Bioequivalence

MRT (hr) MAT (hr) ke (hr-1) ka (hr-1) ug Cp0  -------  mL Vd (L) ug Cp at 1 hour  -------  mL f ug Cpmax  -------  mL Tmax (hr) Relative Bioavailability Generic Equivalent (Yes / No)

1. 2. 3. 4.

MRT iv k e , the elimination rate constant t1 ⁄ 2 Cp 0

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Oral Dosing

5. 6. 7. 8. 9 10. 11. 12. 13.

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

AUC 0 – 1 hour for the iv dose f , the absolute bioavailability of oral zidovudine. MRT oral . MAT oral k a , the apparent absorption rate constant. t peak for the oral dose. Cp max , the maximum concentration of the oral dosage form given as a single dose.

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