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Author: Michael Makoid and John CobbyReviewer: Phillip Vuchetich
OBJECTIVES
After successfully completing this chapter, the student shall be able to
1. Given patient drug concentration and/or amount vs. Time profiles, the student will calculate (III) the relevant pharmacokinetic parameters ( , K, , , , ,
Clearance, MRT, MAT) available from oral data.
2. Given patient drug concentration and/or amount vs. Time profiles, the student will calculate (III) the K from the terminal portion of the curve.
3. Given patient drug concentration and/or amount vs. Time profiles, the student will calculate (III) the from either the curve stripping Moment techniques.
4. Given patient drug concentration and/or amount vs. Time profiles, the student will calculate (III) the Absolute Bioavailability from comparing IV and oral (or some other process which involves absorption) data.
5. Given patient drug concentration and/or amount vs. Time profiles, the student will calculate (III) the Comparative Bioavailability from comparing the generic to the inovator product.
6. Given patient drug concentration and/or amount vs. Time profiles, the student will qualitatively evaluate (IV) bioequivalence as determined by rate of absorption (peak time) and extent of absorption (Area Under the Curve - AUC, and ).
7. Given patient drug concentration and/or amount vs. Time profiles, the student will evaluate (IV) bioequivalence data.
8. Given patient drug concentration and/or amount vs. Time profiles, the student will lucidly discuss (IV) bioequivalence and recommend (V) to another competant professional if s/he believes products to be equivalent.
= the absolute bioavailabilty; the fraction of dose which ultimately reaches sys-temic circulation (which is made up of the fraction of the dose which is absorbedtimes the fraction which gets past the liver (first pass effect))
The following information is available for ampicillin: 90% is excreted unchanged and a 250 mg IV bolus dose yields anAUC of 11 mic/mL*hr. The following blood level profile has been reported for two brands of ampicillin which weregiven as 500 mg oral capsules.
Find the following:.
a. k for both products.
b. for both products.
c. for both products.
d. AUC for both products.
e. for both products.
f. for both products.
g.
h.
i for a 250 mg IV dose.
j.
k. Are these two products bioequivalent? Why or why not?
l. What infusion rate would be necessary to maintain a serum
The data was plotted as above with the best fit line drawn. From the graph the fol-lowing parameters were derived:
2) In a clinical study (DiSanto & DeSante, JPS 64:100,1975) prednisone wasadministered to 22 adult healthy volunteres (average weight 64.5 kg) either as one50 mg tablet (product A) or as ten 5 mg tablets (product B). The following datawas observed:
Can you conclude that these products are bioequivalent ?
No, Time to peak (Tmax) is outside guidelines.
3) Wilkenstein et al.(Gastroenterology 74:360,1978) tested 12 normal healthyvolunteers in a four way crossover design of four dosage forms containing 300 mgof cimetadine. The following data was obtained:
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 toshow up in the urine because only 77% of the IV dose shows up in the urine(.61*.77=.47).
d} Would you consider the oral forms bioequivalent? (No)
Why/Why not? Ratio of peak times ouside guidelines.
e} What infusion rate would you suggest to maintain a plasma concentration of0.75 mic/ml ?
Q = Cpss * K * V = 0.75 mg/L * 0.283 hr^-1 * 125 L = 26.54 mg/hr
f} How long would it take that infusion to attain a therapeutic plasma concentra-tion of 0.5 mic/ml ?
4) LYSERGIC ACID DIETHYLAMIDE (LSD) was given to human volunteers atthe dose of 150 mic orally. (Impregnated blotter dosage form.) The following datawas obtained:
b) An IV dose of 100 mic resulted in an AUC of 20.4 ng/ml*hr. Find f.
c) The volunteers ability to concentrate as measured by their ability to do standardtasks was also monitored. (100% control means no drug interference.) The fol-lowing data was obtained:
Cp (ng/ml) % Control Cp (ng/ml) % Control
5.5 33 1.5 65
4.1 40 1.1 80
2.9 52
If 100 mic dose were given by IV bolus, how long would it be before the volunteerwould regain 80% of his control?
Evaluation of the graph of response vs ln(concentration) yields:
dR/dln(c) = 27.86
Multiplying dR/dln(c) * dln(c)/dt (m of the previous graph) yields dR/dt = 27.86 *-0.225 = 6.26%/hr
100 mic dose IV yields Cp0 of (Cp0 =AUC * K = 20.4 * 0.225) 4.59ng/mL.
The response of a 100 mic dose is (R = 27.86*ln(4.59)+19.9) 62.3%
Response = Response at t=0 - dR/dt * t
20% = 62.3% - 6.26%/hr * t hours
T = 6.76 hours
5. The following data was collected from a double blind cross over study between500 mg dose of cloxacillin made by Bristol (Tegopen@) and a generic productwhich you might want to put in your store.
Actual evaluation of ka and peak time is dificult because of the pucity of data atearly time points however all relavent parameters meet guidlines.
7. The F.D.A. reported the following data submitted to be consideration regardingthe equivalence of Mylan Pharmaceuticals' Tetracycline with that of Lederle andan intervenous bolus dose. (Dose 250 mg).
Would you consider Mylan to be bioequivalent to the Lederle product ?
Calculate the absolute bioavailability of Lederle Tetracycline.(.77)
f) Calculate the volume of distribution of tetracycline. (44.3 L)
g) Tetracycline has a pKa of 9.7. Tetracyclines tend to localize in the dentin andenamel of developing teeth causing hypoplasia and permanent discoloration ofteeth. Would you recomend tetracyline for a 110 pound lactating mother ?
Support your argument with the dose of the child. (Child's weight 11 lbs. and heeats 2 oz of milk every 2 hours. Mom's average plasma concentration is main-tained at 3 mic/ml by taking 250 qid. pH of the milk is 6.1, pH of blood is 7.4)
With only one data point in the early time points, the larger rate constant is in ques-tion. The terminal slope is assumed to be K. The AUC will yield the amount ofketameperidine which was metabolized (dXmu/dt * t = Xmu).
K (hours^-1) 0.216
AUC (mg)30.3
30.3 mg showed up as metabolite = 60.6% of 50 mg dose.
The data is plotted both without (first figure) and with (second figure) a lag-timewhich is associated with the release of the drug from the delivery system. Notethat the addition of the lag-time improves the fit.
It takes the tablet about 20 minutes to release the drug!
Wilkenstein et al.(Gastroenterology 74:360,1978) tested 12 normal healthy volun-teers in a four way crossover design of four dosage forms containing 300 mg ofcimetadine. The following data was obtained: A B C D
AUC(mic/ml x hr) --- --- 5.2 5.4
recovered in urine intact77.177.1 54.9 55.8
Peak serum conc.(mic/ml)--- --- 1.53 1.44
Onset (hr) 0 0.34 0.65
Duration (hr) 4.5 4.6 4.2 4.4
Time to peak (hr) 0 1.0 2.0
A = IV Bolus B=IM injection C = Oral liquid D= Oral tablet
The plasma concentration vs. time profile for product A is as follows:
time (hrs) conc.(ug/ml)
1 1.79
2 1.36
4 0.78
6 0.45
12 0.08
a} find K, Cp0.
Both can be found from the graph. K = .283/hr Cp0 = 2.36 mic/ml
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 thatto show up in the urine because only 77% of the IV dose shows up in the urine(0.61 * .77 = .47).
d} How can you explain the variation in % recovered intact in the urine?
e} Would you consider the oral forms bioequivalent ? Why/Why not?
No. The ratio of peak times is outside the guidelines.
f} What infusion rate would you suggest to maintain a plasma concentration of0.75 mic/ml?
Q = Cpss * K * V = 0.75 mg/L * 0.283/hr * 125L = 26.54 mg/hr
g} How long would it take that infusion rate to attain a therapeutic plasma concen-tration of 0.5 mic/ml ?
Roxane labs of Columbus, Ohio offers the following data for your review of theirQuinidine Sulfate tablets (Dose 200 mg). It is compared against the referencestandard by Ely Lilly and company at the same dose.
e) Comment on which patient might need modification in therapy and why.
The patient with viral hepatitis would need modification in therapy. Becauseof the decrease in TBC, we can see that the drug is staying the body muchlonger than normal, therefore the dosage regimen should be decreased.
Chlorthalidone is used to treat high blood pressure. The following information isoffered regarding a generic
b) Would you consider the generic product to be bioequivalent to the USV(Hygroton@) product? Prepare a short statement that you would tell a patientregarding why you would or would not make a generic substitution for this drug.
No. The maximum concentration the generic is too much greater than that ofthe brand name product.
They are not considered to be bioequivalent.
R(G/H)
Cpmax (mg) 1.23 outside
Time to peak (hr)0.78outside
AUC (0 to inf)115 ok
Buspirone is a new anxiolytic agent that has been found to be effective for thetreatment of generalized anxiety disorder at a mean dose of approximately 20 mg/day orally in divided doses. Buspirone is metabolized almost entirely. Less than0.1% is found intact in the urine. The following data has been presented by Gam-mans (Am J Med:80(supp 3b),41-51;1986):
Valproate is a carboxylic acid anticonvulsant. Its activity may be related, at leastin part, to increase concentrations of the neurotransmitter inhibitor gamma ami-nobutyric acid in the brain. It is used alone or in combination with other anticon-vulsants. in the prophylactic management of petit mal. It appears to be almostentirely cleared by liver function with negligible amounts excreted into the urineunchanged. It comes as soft gelatin capsules of 250 mg and enteric coated tablets250 and 500 mg as well as oral syrup of 250 mg / 5 cc. Two different formula-tions of Valproate (250 mg) were prepared by Abbott and compared. The data is asfollows:
2) Five hundred mg of valproate was administered by IV bolus. The AUC for thatroute was 574 mg/L * hr. Calculate f for formulation A. Calculate Cp0 for the IVdose.
3) Find Peak Time and Cmax for formulation A.
4) Calculate the comparative bioavailability of formulation B.
5) Would you consider formulation B to be bioequivalent to Formulation A ? Pre-pare a short statement in which you would substantiate that stand that you might
d) Would you consider Lederle to be bioequivalent to the Squibb product ?
e) Calculate the absolute bioavailability of Lederle Procainamide.
f) Calculate the volume of distribution of procainamide.
g) Would you recommend your patient breast feed her newborn? Prepare a shortconsult for her physician. Support your argument with the dose of the child.(Child's weight 11 lbs. and he eats 2 oz of milk every 2 hours. Mom's averageplasma concentration is maintained at 4 mic/ml from a 1 g dose ever 6 hours. pH ofthe milk is 6.3, pH of blood is 7.4)
Procainamide is cleared about 60% by liver and 40% by kidney function. 20 % ofcardiac output (70 ml/min/kg) goes to liver, 25% goes to the kidney. Mom'sweight is 130 lb. Assuming her plasma vs time profile to be similar to the Lederleproduct (i.e. pharmacokinetic parameters obtained from this information can beused):
h) Calculate Total body clearance
i) Calculate the intrinsic hepatic plasma clearance of procainamide.
j) Calculate the effect on her total body clearance if she were to contract viral hep-atitis which effect liver function (FI = 0.4). Prepare a short consult for her physi-cian as to whether you would recommend a change in therapy. d) Calculate theeffect on her total body clearance stenosis of the liver (FR = 0.4). Prepare a shortconsult for her physician as to whether you would recommend a change in therapy.
Ratio of kid's daily dose/# to Mother's daily dose/# = (36mg/11#)/(1000mg*4/130#) = 0.42. The kid gets about half of the mother's dose!
Nifedipine (Procardia @) is a calcium channel blocker which specifically inhibitspotential-dependent channels not receptor-operated channels, preventing calciuminflux of cardiac and vascular smooth muscle (coronary, cerebral). Calciumchannel blockers reduce myocardial contractility and A-V node conduction byreducing the slow inward calcium current. They are indicated in angina, cardiacdysrhythmias, and hypertension among others. Nifedipine appears to be metabo-lized entirely into an inactive metabolite, an acid and subsequently further metab-olized to a lactone. Both the acid and the lactone are excreted into the urine andthe feces.
Echizen and Eichelbaum (Clin Pkin 1986; 11:425-49) and Kleinbloesem et al (ClinPcol Therap 1986; 40: 21-8) Reviewed the pharmacokinetics of Nifedipine. Whilethe drug is not routinely given by IV bolus and does not strictly conform to a onecompartment model, lets treat the data as if those problems can be ignored. Thefollowing data is offered for evaluation:
Tetracycline HCl has a pKa of 9.7. Tetracyclines tend to localize in the dentin andenamel of developing teeth causing hypoplasia and permanent discoloration ofteeth. Would you recommend tetracycline for a lactating mother ? Support yourargument with the dose of the child. (Child's weight 11 lbs. and he eats 2 oz ofmilk every 2 hours. Mom's average plasma concentration is maintained at 4 mic/ml she is taking 250 mg T.I.D. ( Milk pH = 6.1, Blood pH = 7.4)
Tm/Tb = 109.7 - 6.1/109.7 - 7.4 = 20/1
The concentrarion of tetracycline in the mother's milk is 80 mic/ml
The child takes in 720 ml of milk per day
80 mic/ml * 720 ml = 57600 mic = 57.6 mg
57.6mg/5kg = 11.52mg/kg = dose that the child is getting from the mother'smilk.
I would not recomend tetracycline for a lactating mother. The dose that a nurs-ing child gets from the milk too high.
Oxazepam (acid, pKa 11.5) is an anxyolytic sedative with the usual adult dose 10mg 3 times daily. If the circulating plasma concentration of oxazapam were 20
mic/ml for nursing 120 lb mother, would her 9 lb infant be getting a comparablemg per kg daily dose if he consumes 2 oz of his mothers milk every 2 hours. Pre-pare a short consult for her physician in which you might (or might not) recom-mend the patient stop breast feeding while she is on this medication. Includeappropriate calculations.
Om/Ob = 1011.5 - 6.1/1011.5 - 7.4 = 20/1
The concentration of the mother's milk would then be 400 mic/ml
400 mic/ml * 720 ml = 288000 mic given to baby = 288mg
288mg / 4.1kg = 70 mg/kg = dose/kg given to baby
This dose is much greater then that given to the mother. The mother shoulddiscontinue breast feeding while taking Oxazepam.
Bioequivalence studies are sometimes done within the same company to check ifthe tablets of the same drug, but different strengths (with the strength normalized)could be considered equivalent (i.e. could two 5 mg tablets be considered equal toone 10 mg tablet). While not strictly kosher (products are not pharmaceuticalequivalents because of different strengths), it is done. Here is the results of such astudy in which Zomax 100 and 200 mg tablets were compared. (Yes, I know thatZomax was removed from the market after a short life of only 6 months.)
10) What is the absorption rate constant for the 100 mg tablet ?
A) 1.7 B) 2.2 *C) 2.6 D) 3.2 E) 3.7
11) What is the intercept of the extrapolated line for the 200 mg tablet ?
A) 3.5 B) 4.1 C) 5.6 D) 6.1 *E) 7.6
12) What is the absorption rate constant for the 200 mg tablet ?
A) 1.7 B) 2.2 C) 2.6 D) 3.2 *E) 4.01
13) What is the Tmax for the 100 mg tablet ?
A) 0.5 B) 0.67 C) 0.75 *D) 0.85 E) 0.95
14) What is the Tmax for the 200 mg tablet ?
A) 0.5 *B) 0.67 C) 0.75 D) 0.85 E) 0.95
15) Would you consider these two tablets bioequivalent (given normalization fordose) (consider all ratios to be the 100 mg / 200 mg parameter normalized as todose where applicable)?
16) What infusion rate would you recommend to maintain an average plasma con-centration of 1 mic/ml ?
A) 17.5 B) 13.3 *C) 11.8 D) 10.4 E) 9.0
Vd = D/Cp0 = 50mg/1.7mg/L = 29.4
Q = Cpss * K * V = 1mg/L * 0.4/hr * 29.4L = 11.8
17) What would be the concentration (mg/L) 2 hrs after discontinuing the infu-sion assuming you reached steady state ?
A) 0.67 B) 0.55 *C) 0.45 D) 0.37 E) 0.30
Cpss = Cp0 * e-Kt
= 1mg/L * e(-0.4 * 2)
= 0.44
A 110 pound mother breast feeds her 11 pound infant while on morphine sulfate(base, pKa = 9.85). Mother's average circulating plasma levels are 0.5 ug/ml fol-lowing a 10 mg IV dose q4h. (pH Milk = 6.1, pH blood = 7.4)
18) What is the Ratio of morphine concentration in the milk as compared to theblood ?
Answers are rounded off. When you pick a foil, use that number in subsequent cal-culations when needed.
Rifampin (unionized free base pKa 7.9) is a drug used to treat TB. The followingdata was collected following a 600 mg oral tablet from the inovator (Treatment A),and a 600 mg oral tablet from a generic (treatment B), and a 400 mg IV dose(Treatment C).
15) The average plasma concentration for the mother (110#) is 2.5 mg/L from a600 mg once a day dosing regimen. If the baby (11#) drinks 780 mL of milk a day(2 - 2.5 ounces every 2 hours), what is his daily dose (mg)?
a) 0.1 b) 0.13 c) 2 d) 30 *e) 39
Mother's blood average blood conc. is 2.5 mg/L therefore her milk conc. is 50mg/L.
If the baby drinks 780 ml of milk he/she will get 39 mg of the drug.
16) Would you recommend mom stop breast feeding? (What % of the mom's dailydose (mg/kg) is the baby's daily dose (mg/kg)?)
a) No, the child's dose is less than 1% of the mother's dose on a mg/kg/day basis.
b) No, the child's dose is about 5% of the mother's dose on a mg/kg/day basis.
c) Maybe, the child's dose is about 10% of the mother's dose on a mg/kg/day basis.
*d) Yes, the child's dose is about 50% of the mother's dose on a mg/kg/day basis.
e) Yes, the child's dose is about the same as the mother's dose on a mg/kg/daybasis.
17) While Rifampin is not administered by IV infusion, what would be the infu-sion rate necessary to maintain an average plasma concentration of 2.5 mg/L (mg/hr)? *a) 25 b) 50 c) 100 d) 150 e) 200
18) While Rifampin is not administered by IV bolus, what would be the loadingdose necessary to obtain a plasma concentration of 2.5 mg/L (mg)? a) 25 b) 50*c) 100 d) 150 e) 200
Loading Dose = Cpss * Vd
= 2.5 * 39.9
= 100mg
19) While Rifampin is not administered by IV infusion, what would be the infu-sion rate necessary to obtain a plasma concentration of 2.5 mg/L in about 2.5 to 3hours (mg/hr)? a) 25 *b) 50 c) 100 d) 150 e) 200
Cp = [Q/(K * Vd)] * (1 - e-kt)
Q = (Cp * K * Vd)/(1 - e-kt)
= (2.5mg/L * 0.25 * 39.9L)/[1 - e(-0.25 * 2.75)]
= 50 mg/hr
20) Rifampin is a semisynthetic derivative of rifamycin B, an antibiotic derivedfrom Streptomyces mediterranei. The minimum inhibitory concentration for N.menengitidis is 0.1 - 1 mic/mL. It is distributed well into bodily fluids. About 30%shows up in the urine as free drug and active metabolite while 60% shows up in thefeces as metabolite. The secretary is hounding me to finish the exam, so theanswer to 20 is a. Also, rifampin is 85% protien bound at physiological concen-trations. *a) 25 b) 50 c) 100 d) 150 e) 200
(2) For each of the following pairs of variables (ordinate against abscissa), drawa graph illustrating the qualitative profile of their relationship. Where appropri-ate, indicate the nature of important slopes, intercepts, and values. Unless yourspecifically indicate on your plot that semi-log paper is being considered (write "S-L"), it will be assumed that rectilinear paper is being considered. Graphs are for adrug given by oral route where applicable.
(2) Compare and contrast:a}Wagner-Nelson and feathering methods b} Treat-ment of plasma and urine data using Wagner-Nelson
(3) For each of the following pairs of variables (ordinate against abscissa), drawa graph illustrating the qualitative profile of their relationship. Where appropri-ate, indicate the nature of important slopes, intercepts, and values. Unless yourspecifically indicate on your plot that semi-log paper is being considered (write "S-L"), it will be assumed that rectilinear paper is being considered. Graphs are for adrug given by oral route where applicable.
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 thedimensions of measurement:
a) clearance b)f c) absolute bioavailability d) comparative bioavailability e)AUC
2. By means of an annotated phase diagram explain how freeze-dried pharmaceuti-cal injectables are made.
3. For each of the following pairs of variables (ordinate against abscissa) draw agraph illustrating the qualitative profile of their relationship. Where appropriate,indicate the nature of important slopes, intercepts, and values. Unless you specifi-cally indicate on your plot that semi-log paper is being considered (write "SL"), itwill be assumed that rectilinear paper is being considered.
Pharmacological Response vs time
Peak time vs ka for oral dose
Fractional change in total body clearance vs. renal clearance
1. Succinctly define, stating rigorously the meaning of any symbols used and thedimensions 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 polymorphcan be formed and how these polymorphs might effect the bioavailability of thedrug.
3. For each of the following pairs of variables (ordinate against abscissa) draw agraph illustrating the qualitative profile of their relationship. Where appropriate,indicate the nature of important slopes, intercepts, and values. Unless your specif-ically indicate on your plot that semi-log paper is being considered (write "S-L"),it will be assumed that rectilinear paper is being considered
fractional change in total body clearance vs plasma flow for drugs having a largeextraction ratio.
Peak time vs ka for oral dose
Fractional change in total body clearance vs. hepatic clearance.
1. Succinctly define, stating rigorously the meaning of any symbols used and thedimensions of measurement:
Henderson-Hasselbach relationship
Therapeutic alternatives
Therapeutic equivalents
comparative bioavailability
Extraction ratio
Briefly discuss generic substitution by the pharmacist. Include such topics as whenit might be admissable and the liabilities involved.
3. For each of the following pairs of variables (ordinate against abscissa) draw agraph illustrating the qualitative profile of their relationship. Where appropriate,indicate the nature of important slopes, intercepts, and values. Unless you specif-ically indicate on your plot that semi-log paper is being considered (write "S-L"),it will be assumed that rectilinear paper is being considered
a) fractional change in total body clearance vs fractional change in plasmaflow for drugs having a small extraction ratio.
c) Fractional change in total body clearance vs. fractional change in hepaticclearance for drugs having a large extration ratio.
d) Ratio of milk to blood for basic drugs vs pKa.
e) Ratio of milk to blood for acidic drugs vs pKa.
PHARMACOKINETICS SECOND HOUR PRACTICE EXAM #7
SECTION I
1. Succinctly define, stating rigorously the meaning of any symbols used and thedimensions 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 agraph illustrating the qualitative profile of their relationship. Where appropriate,indicate the nature of important slopes, intercepts, and values. Unless you specif-ically indicate on your plot that semi-log paper is being considered (write "S-L"),it will be assumed that rectilinear paper is being considered
d) TBC vs Fi(H) for a drug with a high extraction ratio in the liver.
e) TBC vs Fr(H) for a drug with a high extraction ratio in the liver
PHARMACOKINETICS SECOND HOUR PRACTICE EXAM #9
SECTION I
1. Succinctly define, stating rigorously the meaning of any symbols used and thedimensions 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 aswhen it might be admissible and the liabilities involved.
3. For each of the following pairs of variables (ordinate against abscissa) draw agraph illustrating the qualitative profile of their relationship. Where appropriate,indicate the nature of important slopes, intercepts, and values. Unless you specifi-cally indicate on your plot that semi-log paper is being considered (write "SL"), itwill be assumed that rectilinear paper is being considered
a) fractional change in total body clearance vs fractional change in plasmaflow for drugs having a small extraction ratio.
c) Fractional change in total body clearance vs. fractional change in intrinsichepatic clearance for drugs having a large extraction ratio.
d) Ratio of blood to milk concentrations for basic drugs vs pKa.
e) Ratio of blood to milk concentrations for acidic drugs vs pKa.
PHARMACOKINETICS SECOND HOUR PRACTICE EXAM # 10
SECTION I
1. Succinctly define, stating rigorously the meaning of any symbols used and thedimensions 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 agraph illustrating the qualitative profile of their relationship. Where appropriate,indicate the nature of important slopes, intercepts, and values. Unless you indicateon your plot that semi-log paper is being considered (write SL), it will be assumedthat rectilinear paper is being considered. Graphs are for a drug given by an oraldelivery system where applicable.
Quigano, R., et al., "Effect of atropine of gastrointestinal motility and the bioavailability of cyclosporine A in rats", Drug Metabo-lism and Disposition, Vol. 21, No. 1, (1993), p. 141 - 143.
In this study rats with an average weight of 300 g were given either an IV bolus dose of cyclosporine A (CyA)or an oral dose of CyA. Subsequently, doses of atropine were given; however, the data below is that which was gath-ered prior to atropine administration. A summary of the some of data obtained from this experiment is given below.
From the preceding data, please calculate the following:
1.
2. , the elimination rate constant
3.
Parameter IV Oral Solution Brand Tablet Generic Tablet Bioequivalence
Gehr, T., et al., "The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients", European Journal of Clin-ical Pharmacology, Vol. 45, No. 5, (1993), p. 431 - 436.
Fosinopril (MW 562.6) is a new Angiotension Converting Enzyme (ACE) Inhibitor used in the treatment ofhypertension. Following oral administration, fosinopril is rapidly and almost completely hydrolyzed to its pharmaco-logically active metabolite, fosinoprilate (MW 435.2). About 50% of the drug is excreted unchanged through the kid-neys. In this study, patients received either 7.5 mg of fosinoprilat administered intravenously or 10 mg of fosinopriladministered orally. A summary of the some of data obtained from this experiment is given below.
From the preceding data, please calculate the following:
1.
2. , the elimination rate constant
Parameter IV Oral Solution Brand Tablet Generic Tablet Bioequivalence
Rutledge, D., Pieper, J., and Mirvis, D., "Effects of chronic phenobarbital on verapamil disposition in humans", The Journal of Pharmacology and Experimental Therapeutics, Vol. 246, No. 1, (1988), p. 7 - 13.
This study focused on the effects of phenobarbital, a hepatic-enzyme inducer, on verapamil. Seven healthymale volunteers with an average weight of 78.8 kg participated in the study. The patients received either an single oralverapamil dose of 80 mg or a single intravenous verapamil dose of 0.15 mg/kg over 3 minutes. A summary of the someof data obtained from this experiment is given below.
From the preceding data, please calculate the following:
1.
2. , the elimination rate constant
3.
Parameter IV Oral Solution Brand Tablet Generic Tablet Bioequivalence
Trang, J., et al., "Zidovudine bioavailability and linear pharmacokinetics in female B6C3F1 mice", Drug Metabolism and Disposi-tion Vol, 21 (1993), p.189 - 193.
Zidovudine (AZT) is a potent inhibitor of HIV-1 during viral replication. It has been approved for the treat-ment of AIDS. In this study a 30 mg/kg dose of AZT was given to mice either iv or orally. :A summary of the someof data obtained from this experiment is given below.
From the preceding data, please calculate the following:
1.
2. , the elimination rate constant
3.
4.
Parameter IV Oral Solution Brand Tablet Generic Tablet Bioequivalence