Oral Dosing
CHAPTER 7




                                                                                                ...
Oral Dosing




                                  9.       The student shall be able to properly use vocabulary relative t...
Oral Dosing




7.1 Oral dosing

7.1.1                     VALID EQUATIONS: ( ORAL DOSING, PLASMA)

                      ...
Oral Dosing




                                                    Ampicillin                                          (P...
Oral Dosing




                                            plasma concentration of 2mcg/mL



                           ...
Oral Dosing




                                  0.5                         40.8                57.3

                  ...
Oral Dosing




                                                                        Product A            Product B    ...
Oral Dosing




                                                                        A         B          C      D

   ...
Oral Dosing




                                  f} What infusion rate would you suggest to maintain a plasma concentrati...
Oral Dosing




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



                   ...
Oral Dosing




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

     ...
Oral Dosing




                                  Evaluation of the graph of Concentration vs. time yields:



           ...
Oral Dosing




                                  m (-K)             -0.225 hr^-1

                                  Ka   ...
Oral Dosing




                                  0.25        .41       0.1      1.5        6.93        7.75

            ...
Oral Dosing




                                  Evaluation of the above graphs yields:

                                ...
Oral Dosing




                                  3       2.65 2.25 3.4           15          0.50 0.45 0.46



          ...
Oral Dosing




                                  Pharmacokinetic parameters:

                                           ...
Oral Dosing




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




   ...
Oral Dosing




                                            5.0 - 7.0                   1.47

                            ...
Oral Dosing




                                  kr = K - km = 0.085 hours^-1

                                  Aminophy...
Oral Dosing




                                  Answer:

                                  AUC (mg/L)*hr117.8

         ...
Oral Dosing




                                  Infusion rate = Q = Cpss * TBC = 15 mg/L * 2.83 L/hr = 42.45 mg/hr Theop...
Oral Dosing




                                  The data is plotted both without (first figure) and with (second figure)...
Oral Dosing




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



           ...
Oral Dosing




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

            ...
Oral Dosing




                                           Time (hours)Concentration (mcg/ml)

                           ...
Oral Dosing




                                                                                                    7-27
B...
Oral Dosing




                                                              Roxane labsEli Lilly

                      ...
Oral Dosing




                                  a) find ka

                                  b) Calculate the absolute ...
Oral Dosing




                                                                 IV data             Oral Data

          ...
Oral Dosing




                                  a) Calculate TBC

                                       TBC = K * V = (...
Oral Dosing




                                           (hours)            Hygroton@Generic

                          ...
Oral Dosing




                                           Average mean83.1             84.5

                            ...
Oral Dosing




                                           0.25               --                  1.07

                  ...
Oral Dosing




                                                              IV        Oral

                            ...
Oral Dosing




                                           Time(Hr.)Formulation BFormulation A

                          ...
Oral Dosing




                                  need to respond to another health professional who asked you to stock th...
Oral Dosing




                                  Comparative bioavailability =(AUCb/DOSEb)/(AUCa/DOSEa) = 243.3/287 =
   ...
Oral Dosing




                                  a) find ka of the Squibb product

                                  b) k...
Oral Dosing




                                                     IV        LederleSquibb R(L/S)

                     ...
Oral Dosing




                                   = 0.86



                                  Vd = Dose/Cp0 = 0.87*250mg/...
Oral Dosing




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

   ...
Oral Dosing




                                                     IV       A         B         R(A/B)

                ...
Oral Dosing




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

        ...
Oral Dosing




                                  mic/ml for nursing 120 lb mother, would her 9 lb infant be getting a com...
Oral Dosing




                                  2        1.56      3.49               3.37      8.33              0.764
...
Oral Dosing




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

               ...
Oral Dosing




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

      ...
Oral Dosing




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

                     ...
Oral Dosing




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

                             ...
Oral Dosing




                                                     IV       Tablet Tablet

                             ...
Oral Dosing




                                  Answers are rounded off. When you pick a foil, use that number in subseq...
Oral Dosing




                                            (mic/mL*hr)

                                  Lag time (min)1...
Oral Dosing




                                  4) What is the elimination rate constant for rifampin (hr^-1)? *a) 0.25 ...
Oral Dosing




                                  11) Calculate the peak time for the generic product (min).              ...
Oral Dosing




                                          = 20



                                  15) The average plasma...
Oral Dosing




                                     Q = Cpss * K * Vd

                                       = 2.5 * 0.2...
Oral Dosing




                                                     A        B         IV

                              ...
Oral Dosing
Oral Dosing
Oral Dosing
Oral Dosing
Oral Dosing
Oral Dosing
Oral Dosing
Oral Dosing
Oral Dosing
Oral Dosing
Oral Dosing
Oral Dosing
Oral Dosing
Oral Dosing
Oral Dosing
Oral Dosing
Oral Dosing
Oral Dosing
Oral Dosing
Oral Dosing
Oral Dosing
Oral Dosing
Upcoming SlideShare
Loading in …5
×

Oral Dosing

2,953 views

Published on

Oral Dosing

Published in: Health & Medicine
1 Comment
0 Likes
Statistics
Notes
  • Be the first to like this

No Downloads
Views
Total views
2,953
On SlideShare
0
From Embeds
0
Number of Embeds
4
Actions
Shares
0
Downloads
100
Comments
1
Likes
0
Embeds 0
No embeds

No notes for slide

Oral Dosing

  1. 1. Oral Dosing CHAPTER 7 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. 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 k a 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 ( Cp ) max ). 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. 7-1 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  2. 2. Oral Dosing 9. The student shall be able to properly use vocabulary relative to bioequivalence. 7-2 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  3. 3. Oral Dosing 7.1 Oral dosing 7.1.1 VALID EQUATIONS: ( ORAL DOSING, PLASMA) ka –k t C p = fD ⋅ -------------- ⋅ ( e – e a ) – Kt ----- - - (EQ 5-18) Vd k a – K AUC ( oral ) ⁄ Dose ( oral ) f = -------------------------------------------------------------- (EQ 5-19) AUC ( iv ) ⁄ Dose ( iv ) AUC ( generic ) ⁄ Dose ( generic ) - CB = ------------------------------------------------------------------------------------- (EQ 5-20) AUC ( inovator ) ⁄ Dose ( inovator ) ln ( k a ⁄ K ) t p = ----------------------- (EQ 5-21) ( ka – K ) Xa ----- = K ⋅ AUC ∞ – ( C p + K ⋅ AUC t ) - (EQ 5-22) v where = the comparative bioavailability CB f = 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 absorbed times the fraction which gets past the liver (first pass effect)) = absorption rate constant. ka 7.1.2 UTILIZATION 7-3 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  4. 4. 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 µg MEAN SERUM LEVEL ------- - mL Time (hr) 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 Find the following:. a. k for both products. b. k a for both products. c. k u for both products. d. AUC for both products. e. f for both products. f. t max for both products. g. Cl h. Vd i Cp 0 for a 250 mg IV dose. j. Cp max k. Are these two products bioequivalent? Why or why not? l. What infusion rate would be necessary to maintain a serum 7-4 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  5. 5. 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: TABLE 4-8 Comparison of Ampicillin Lederle Bristol Ratio (L/B) 0.688 0.635 –1 K ( hr ) 0.858 0.831 –1 K a ( hr ) T max ( hr ) 1.74 1.8 0.97 ( C p ) max ( µg ⁄ mL ) 3 2.9 1.03 AUC (trapaziodal) 11.4 11.6 0.98 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) Concentration (mic/100ml plasma) A B 7-5 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  6. 6. 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: 7-6 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  7. 7. 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 healthy volunteers in a four way crossover design of four dosage forms containing 300 mg of cimetadine. The following data was obtained: 7-7 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  8. 8. 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? 7-8 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  9. 9. 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 con- centration of 0.5 mic/ml ? Answer: IV Bolus Parameters: Cp max2.4 mic/mL AUC 8.5 K 0.283 hr^-1 7-9 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  10. 10. 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 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)) --> 3.9 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: 7-10 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  11. 11. 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 standard tasks 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 volunteer would regain 80% of his control? Answwer: 7-11 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  12. 12. 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 7-12 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  13. 13. 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 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 7-13 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  14. 14. 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: 7-14 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  15. 15. 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 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) 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 7-15 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  16. 16. 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 main- tained at 3 mic/ml by taking 250 qid. pH of the milk is 6.1, pH of blood is 7.4) Answer: 7-16 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  17. 17. 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. 7-17 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  18. 18. 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 urinary profile 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 7-18 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  19. 19. 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 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 7-19 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  20. 20. 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 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. 7-20 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  21. 21. 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 7-21 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  22. 22. 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: 7-22 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  23. 23. 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 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 7-23 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  24. 24. 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 of cimetadine. 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 7-24 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  25. 25. 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 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 their Quinidine Sulfate tablets (Dose 200 mg). It is compared against the reference standard by Ely Lilly and company at the same dose. 7-25 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  26. 26. 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 Lilly product ? Answers 7-26 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  27. 27. Oral Dosing 7-27 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  28. 28. 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 7-28 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  29. 29. Oral Dosing a) find ka b) Calculate the absolute bioavailability of propranolol. c) Calculate TBC 7-29 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  30. 30. 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. 7-30 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  31. 31. 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) 7-31 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  32. 32. 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 7-32 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  33. 33. 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 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 Gam- mans (Am J Med:80(supp 3b),41-51;1986): Time (hours)Concentration (ng/ml) (hours) 1 mg I.V.20 mg oral 7-33 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  34. 34. 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: 7-34 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  35. 35. 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 least in 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 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 formula- tions of Valproate (250 mg) were prepared by Abbott and compared. The data is as follows: 7-35 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  36. 36. 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 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 ? Pre- pare a short statement in which you would substantiate that stand that you might 7-36 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  37. 37. 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 7-37 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  38. 38. 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% 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 7-38 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  39. 39. 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 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 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 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: 7-39 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  40. 40. Oral Dosing IV LederleSquibb R(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 Absolute bioavailability, f,=(AUCoral/DOSEoral)/(AUCiv/DOSEiv) = 7.4 / 8.57 7-40 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  41. 41. 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 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 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 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 7-41 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  42. 42. 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 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: 7-42 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  43. 43. 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. 7-43 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  44. 44. 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 nurs- ing 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 7-44 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  45. 45. 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. 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. 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 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 7-45 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  46. 46. 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 7-46 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  47. 47. 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 7-47 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  48. 48. 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 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 7-48 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  49. 49. 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 the blood ? A) 0.05 B) 0.5 C) 1 D) 2 *E) 20 7-49 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  50. 50. 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 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: 7-50 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  51. 51. 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. 7-51 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  52. 52. 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 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 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 7-52 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  53. 53. 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) 40 d) 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 7-53 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  54. 54. 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) 1.43 d) 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 7-54 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  55. 55. 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) 7-55 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  56. 56. Oral Dosing = 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 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 7-56 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  57. 57. 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 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 infu- sion 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 concen- trations. *a) 25 b) 50 c) 100 d) 150 e) 200 Answers: 7-57 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
  58. 58. 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 7-58 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/

×