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Dosage Regimen (Healthy,Aged, & Diseased Patients)

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- 1. Dosage Regimen (Healthy, CHAPTER 10 Aged, and Diseased Patients) Author: Michael Makoid Reviewer: Phillip Vuchetich OBJECTIVES 1. Given population average patient data, the student will devise (V) dosage regi- mens which will maintain plasma concentrations of drug within the therapeutic range. 2. Given specific patient information, the patient will justify (VI) dosage regimen recommendations. 3. Given patient information regarding organ function, the student will devise (V) and justify (VI) dosage regimen recommendations for the compromised patient. 4. The student will write (V) a professional consult using the above calculations 10-1 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 2. Dosage Regimen (Healthy, Aged, and Diseased Patients) 10.1 Therapeutic Drug Monitoring 10.1.1 THERAPEUTIC RANGE The pharmacokinetics of a drug determine the blood concentration achieved from a prescribed dosing regimen. During multiple drug dosing, the blood concentration will reflect the drug concentration at the receptor site; and it is the receptor site concentration that determines the intensity of the drug’s effect. Therefore, in order to predict a patient’s response to a drug regimen, both the pharmacokinetics and pharmacological response characteristics of the drug must be understood. There exists a fundamental relationship between drug pharmacokinetics and phar- macologic response. The relationship between response and ln-concentration is sigmoidal. A threshold concentration of drug must be attained befor any response is ellicited at all. Therapy is accheived when the desired effect is attained because the required concentration has been reached. That concentration would set the lower limit of utility of the drug, and is called Effective Concentration (MEC). Most drugs are not “clean”, that is exhibit only the desired therapeutic response. They also exhibit undesired side effects, sometimes called toxic effects at a higher, hopefully a lot higher, concentration. At some concentration, these toxic side effects become become intollerable. That concentration, or one below it, would set the upper limit of utility for the drug and is called the Maximum Therapeutic Concentration or Minimum Toxic Concentration (MTC). Patient studies have generated upper (MTC) and lower (MEC) plasma concentration ranges that are deemed safe and effective in treating specific disease states. These concentrations are known as the “therapeutic range” for the drug (see Table 10-1).When a drug is administered at a fixed dosage to numerous subjects, the blood concentrations achieved vary greatly due to biological variation. However it is possible to have a reasomable Clinically, digoxin concentrations below 0.8 ng ⁄ ml will elicit a subtherapeutic effect. Alternatively, when the digoxin concentration exceeds 2.0 ng ⁄ ml side effects occur (nausea and vomiting, abdominal pain, visual disturbances). Drugs like digoxin possess a narrow therapeutic index because the concentrations that 10-2 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 3. Dosage Regimen (Healthy, Aged, and Diseased Patients) may produce toxic effects are close to those required for therapeutic effects. The importance of considering both pharmacokinetics and pharmacodynamics is clear. TABLE 10-1. Average therapeutic drug concentration DRUG RANGE 0.8-2.0 ng ⁄ ml digoxin 2-10 µg ⁄ ml l gentamicin 1-4 µg ⁄ ml lidocaine 0.4-1.4 mEq ⁄ L lithium 10-20 µg ⁄ ml phenytoin 10-30 µg ⁄ ml phenobarbitol 4-8 µg ⁄ ml procainamide 3-6 µg ⁄ ml quinidine 10-20 µg ⁄ ml theophylline Note that drug concentrations may be expressed by a variety of units. Pharmacokinetic factors that cause variability in plasma drug concentration are: • Drug-drug interaction • patient disease state • physiological states such as age, weight, sex • drug absorption variation • differences in the ability of a patient to metabolize and eliminate the drug If we were to give an identical dose of drug to a large group of patients and then measure the highest plasma drug concentration we would see that due to individual variability, the resulting plasma drug concentrations differ. This variability can be attributed to factors influencing drug absorption, distribution, metabolism, and excretion. Therefore, drug dosage regimens must take into account any disease altering state or physiological difference in the individual. Therapeutic drug monitoring optimizes a patient’s drug therapy by determining plasma drug concentrations to ensure the rapid and safe drug level in the therapeu- tic range. 10-3 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 4. Dosage Regimen (Healthy, Aged, and Diseased Patients) • Assays for determination of the drug concentration in plasma Two components make up the process of • Interpretation and application of the resulting concentration data to develop a safe and effective therapeutic drug drug regimen. monitoring: The major potential advantages of therapeutic drug monitoring are the maximiza- tion of therapeutic drug benefits and the minimization of toxic drug effects. The formulation of drug therapy regimens by therapeutic drug monitoring involves a process for reaching dosage decisions. 10.1.2 THERAPEUTIC MONITORING: WHY DO WE CARE? The usefulness of a drug’s concentration vs. time profile i based on the observation that for many drugs there is a relationship between plasma concentration and ther- apeutic response. There is a drug concentration below which the drug is ineffec- tive, the Minimum Effective Concentration (MEC), and above which the drug has untoward effects, the Minimum Toxic Concentration (MTC). That defines the range in which we must attempt to keep the drug concentration (Therapeutic Range). The data in Table 10-1 are population averages. Most people respond to drug con- centrations in these ranges. There is always the possibility that the range will be different in an individual patient. For every pharmacokinetic parameter that we measure, there is a population aver- age and a range. This is normal and is called biological variation. People are differ- ent. In addition to biological variation there is always error in the laboratory assays that we use to measure the parameters and error in the time we take the sample. Even with these errors, in many cases, he therapy is better when we attempt to monitor the patient’s plasma concentration to optimize therapy than if we don’t. This is called therapeutic monitoring. If done properly, the plasma concentrations are rapidly attained and maintained within the therapeutic range throughout the course of therapy. This is not to say all drugs should be monitored. Some drugs have a such a wide therapeutic range or little to no toxic effects that the concentra- tions matter very little. Therapeutic monitoring is useful when: • a correlation exists between response and concentration • the drug has a narrow therapeutic range • the pharmacological response is not easily assessed • there is a wide inter-subject range in plasma concentrations for a given dose In this era of DRGs, where reimbursement is no longer tied to cost, therapeutic monitoring of key drugs can be economically beneficial to an institution. A recent study (DeStache 1990) showed a significant difference with regard to days in the 10-4 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 5. Dosage Regimen (Healthy, Aged, and Diseased Patients) hospital between the patients on gentamicin who were monitored (and their dosage regulated as a consequence) vs. those who were not. With DRGs the hospital was reimbursed a flat fee irrespective of the number of days the patient stayed in the hospital. If the number of days cost less than what the DRG paid, the hospital makes money. If the days cost more than the hospital loses money. This study showed that if all patients in the hospital who were on gentamicin were monitored, the hospital would save $4,000,000. That’s right FOUR MILLION per year. I would say that would pay my salary, with a little left over, and that is only one drug! • The process of First the MD must order the blood assays. therapeutic monitoring • Second, someone (nurse, med tech, you) must take the blood. takes effort. • Someone (lab tech, you) must assay the drug concentration in the blood. • You must interpret the data • You must communicate your interpretation and your recommendations for dosage regimen change to the MD. This will allow for informed dosage decisions. • You must follow through to ensure proper changes have been made. • You must continue the process throughout therapy. Therapeutic monitoring, in many cases, will be part of your practice. It can be very rewarding Thus, if we have deterimined the therapeutic range, we could use pharmacokinet- ics to determine the optimum dosage regemin to maintain the patient’s plasma con- centration within that range. 10.1.3 STEADY STATE It is rare that a drug is given only once. Most therapies consist of multiple doses of several days duration, if not several years. It is necessary, therefore, to be able to asess plasma concenterations, both the peak which much be at or below the MTC and the trough which must be at or above the MEC for the drug to be effec- tive under these conditions. Thus when we dose a patient, the concentration pro- file must be within the Therapeutic Range during the entire time that the patient is taking the drug. We can calculate the plasma concentrations in the followin man- ner. In the simplest model, suppose we give a drug by IV Bolus (because the math is simpler). The equation which would result be = -- ⋅ e D ( – kt) ( –kt ) Cp = Cp 0 ⋅ e (EQ 10-1) I.V. Bolus Multiple Dose -- V The peak would be 10-5 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 6. Dosage Regimen (Healthy, Aged, and Diseased Patients) (EQ 10-2) D 1 Cp max = -- -- V τ If we allowed the drug to be eliminated for hours, the trough would be: D ( –( k ⋅ τ ) ) 1 Cp min = --- ⋅ e - (EQ 10-3) V Upon giving a second dose, prior to the complete removal by the body of the first dose the Cp max 2 would be the second dose plus what was left from the first dose: D ( – ( k ⋅ τ ) ) Cp max = -- + --- ⋅ e D 2 -- - (EQ 10-4) V V ( –(k ⋅ τ )) 2 2 and the would be times , thus: Cp min Cp max e ( –( k ⋅ τ ) ) D ( –( 2k ⋅ τ ) ) : Cp min = D ⋅ e 2 + ---- ⋅ e --- - (EQ 10-5) V V n After n doses, the would be: Cp max (–( k ⋅ τ) ) ( – ( ( n – 1 )k ⋅ τ ) ) Cp max = D + D ⋅ e +…+D⋅e n --- -- - -- -- -- (EQ 10-6) VV V n while the would be: Cp min (–( k ⋅ τ) ) D ( – ( 2k ⋅ τ ) ) ( – ( nk ⋅ τ ) ) Cp min = D ⋅ e +…+D⋅e n + --- ⋅ e --- - - --- - (EQ 10-7) V V V Subtracting equation 10-7 from equation 10-6 to eliminate the series yields: Cp max – Cp min = --- – --- ⋅ e D ( – ( nk ⋅ τ )) D – ( nk ⋅ τ ) D n n = -- ⋅ ( 1 – e ) - - -- (EQ 10-8) V V V –( k ⋅ τ ) n n Cp max ⋅ e is also which means that Cp min –( k ⋅ τ ) –( k ⋅ τ ) n n n n n Cp max – Cp min = Cp max – Cp max ⋅ e = Cp max ( 1 – e ) (EQ 10-9) n Equating equation 10-8 and equation 10-9 and solving for yields: Cp max –( nk ⋅ τ ) Cp max = D ⋅ 1 – e n --- ---------------------------- - (EQ 10-10) V 1 – e–(k ⋅ τ ) At large n, e – ( nk ⋅ τ ) ⇒ 0 and thus the steady state maximum, ss , is: Cp max 10-6 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 7. Dosage Regimen (Healthy, Aged, and Diseased Patients) = D ⋅ ------------------------- 1 ss Cp max -- -- (EQ 10-11) V 1 – e–( k ⋅ τ ) ss and the steady state minimum, , is : Cp min –( k ⋅ τ ) D e ss = -- ⋅ ------------------------- Cp min -- (EQ 10-12) V 1 – e –( k ⋅ τ ) In order to make a general equation set from equation 10-11 and equation 10-12, τ let N be the number of half lives in a dosing interval, , and N = --------- t1 ⁄ 2 N = 1 –(k ⋅ τ ) –( k ⋅ τ ) k = ( ln ( 2 ) ) ⁄ t 1 ⁄ 2 . Substituting into the function , yields and e e -- - 2 thus equation 10-11 becomes: = D ⋅ -------------------- 1- ss Cp max -- -- (EQ 10-13) 1N V 1 – -- - 2 and equation 10-12 becomes : N 1 -- - 2 D ⋅ -------------------- ss Cp min = -- -- - (EQ 10-14) 1N V 1 – -- - 2 The average drug concentration under these conditions would be equivalant to the steady state concentration attained by an infusion of the same rate, i.e. if we were to give a multiple dose at 200 mg every four hours (q4h) or 400 mg every eight hours (q8h), the average that would be attained would be equivelaent to the steady state plasma concentration attained by giving an infusion at 50 mg/hr, (Q = 50 mg/ Q D ss hr), and thus, in the infusion, the and in multiple dosing , and Cp = ---------- Q = --- - k⋅V τ k ⋅ τ = 0.693 ⋅ N so: 1.443 ⋅ D ss D D Cp = ------------------ = ----------------------------- = --------------------- - - - (EQ 10-15) V ⋅ K ⋅ τ V ⋅ 0.693 ⋅ N N⋅V avg Similar equations, although more complex, can be derived for multiple dose oral Oral Multiple Dosing (Approximation) products. However, if we were agreed to live with some error these equations, with some modifications could be used to approximate multiple dose oral products. The error on both calculated Cp maxss and Cp minss would be in the direction of safety, i.e. the calculated Cp maxss would be higher and the calculated Cp minss would be lower that their respective multiple dose oral calculations. Thus, if the simpler 10-7 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 8. Dosage Regimen (Healthy, Aged, and Diseased Patients) equations place the Cp max ss and C minss within the Therapeutic Range, the oral multi- ple dose equations would also. The two modifications would be to the Dose. Bio- availability, f, must be considered, and if the drug given is not the drug measured in the blood, the salt factor, S, the difference in the molecular weight of the two com- MW measured pounds must be taken into account, (i.e. ). Thus, when amino- S = ------------------------------ - MW given phyline, which is a complex consisting of two theophyline molecules and an ethylinedyamine molecule is given, but theophyline is measured, the salt factor, MW Theo 2 ⋅ 180.17 . Thus for oral multiple dose, we can approximate S = ----------------------- = ----------------------- = 0.857 - - MW Amino 420.44 for using IV bolus equations as such : S⋅f⋅D 1 ss = ----------------- ⋅ -------------------- Cp max - - (EQ 10-16) N V 1 – 1 -- - 2 S⋅f⋅D S⋅f⋅D 1.443 ⋅ S ⋅ f ⋅ D ss Cp = ------------------ = ----------------------------- = ----------------------------------- - - - (EQ 10-17) V ⋅ K ⋅ τ V ⋅ 0.693 ⋅ N N⋅V avg N 1 -- - S⋅f⋅D 2 ss = ----------------- ⋅ -------------------- Cp min - - (EQ 10-18) 1N V 1 – -- - 2 because errors involved with this approximation both in maximum and minimum calculations (peak and trough) place the drug further within the Therapeutic Range, i.e. the real peaks are lower than the calculated peaks and the real troughs are higher than the calculated troughs, thus both errors are on the side of safety. The object of pharmacokinetics is to optimize therapy. By definition, that is to Dosing Interval maintain the plasma concentration of the drug within the therapeutic range for the duration of the therapy presuming that is needed. Thus, the concentrations must stay within the MTC and MEC or ss Cp max N MTC ------------ = ------------------- = 2 max - (EQ 10-19) ss MEC Cp min by deviding equation 10-18 into equation 10-16 and simplifying. Given these lim- its, the maximum dosing interval, τmax , is obtained by solving for Nmax: 10-8 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 9. Dosage Regimen (Healthy, Aged, and Diseased Patients) Ln ------------ MTC - MEC N max = ------------------------- - (EQ 10-20) Ln2 τ max and since by definition, N max = ---------- - t1 ⁄ 2 τ max = N max ⋅ t1 ⁄ 2 (EQ 10-21) τ maxis not necessarily the dosing interval of choice, but it is the maximum dosing interval attainable without sustained or controlled release delivery systems. Accepable dosing intervals are those which result in a dose being given at the same time of the day, every day. Imagine, if you will, the chaos on the nursing floor if the dose for a given drug were every 15 hours. Compliance, none too high when the patient is given a reasonable dosing interval, would go straight to the toilet if we asked the patient to take a tablet every 5.3 hours. What would be optimal would be to tie the takeing of the drug with an activity that occurs the same time every day for once a day therapy, or at least dose the same time every day. Thus, for multiple daily doses, the only regimens that work are those which when devide into 24 hours give unit answers: QD = 24/1 = q24h; BID = 24/2 = q12h, TID = 24/ 3 = q8h; QID = 24/4 = q6h; q4h; q3h; q2h. These result in decreasing orders of patient compliance (unless the patient is really motivated to take the drug every 2 hours - forget it.) Thus the maximum acceptable dosing interval would be the larg- est acceptable dosing interval below the τ max . So, for example if τ max is 15.7 hours, the maximum acceptable dosing interval would be 12 hours. we could also dose every 8, 6 or 4 hours if necessary. 10-9 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 10. Dosage Regimen (Healthy, Aged, and Diseased Patients) 10.2 Diseases - Dosing the Compromised Patient As previously discussed in the chapter on clearance, diseases result in changes in clearance. These are routinely as a consequence of changes in organ function or blood flow to the organ. Diseases which cause a change in clearance, do so by changing either the elimination rate constant, K, or the volume of distribution, Vd, or both. Thus the fractional change in total body clearance : Cl tot ∗ ∗∗ F Cl tot = -------------- = K ⋅ V - ----------------- (EQ 10-22) K⋅V Cl tot 0.80 < F Cl < 1.2 , Where X* indicates new or changed variable. In general, if tot changes in dosage regimen are not necessary. In order to return a previously con- trolled healthy pateint back to the therapeutic range, a general rule of thumb is sug- gested as an initial starting point. The desease modifies K (as t1/2) and V. As pharmacists, we can modify D and τ . These variables are paired in the above S⋅f⋅D equations (equation 10-16 and equation 10-18), D with V (in ) and ----------------- - t1 ⁄ 2 V τ τ with (in ). If the physiological change is a change in V, the pharmacist N = --------- t1 ⁄ 2 would recommend a change in D proportionally, and if the half life changes, the pharmacist would recommend a change in the dosing interval proportionally. Remenber, the object is to get the plasma concentrations back to where they were prior to the illness. The only problem is that we are limited to these recommended changes being incremental and not continuous. That is a change in dose is limited to the available dosage forms and strengths and a change in dosing interval is limeted to the accepatable dosing interval. If the drug is highly protein bound, the object would be to get the free concentra- Protein Binding tion back to what it was prior to illness. Consequently, equation 10-16, equation 10-17, and equation 10-18 would be rewritten thus: fu ⋅ S ⋅ f ⋅ D ss ss 1 = f u ⋅ Cp = -------------------------- ⋅ -------------------- Cp (EQ 10-23) 1 – 1 N V max free max -- - 2 fu ⋅ S ⋅ f ⋅ D fu ⋅ S ⋅ f ⋅ D ss ss = fu ⋅ C p Cp = -------------------------- = ----------------------------- - (EQ 10-24) V⋅K⋅τ V ⋅ 0.693 ⋅ N avg free avg 10-10 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 11. Dosage Regimen (Healthy, Aged, and Diseased Patients) N 1 -- - fu ⋅ S ⋅ f ⋅ D ss 2 ss = fu ⋅ Cp = -------------------------- ⋅ -------------------- Cp (EQ 10-25) N V 1 – 1 min free min -- - 2 Some interesting and unexpected things result from these relationships. Since plasma or blood concentrations are usually measured, if a drug is highly protein bound and the desease results in upsetting that equilibrium, you might see toxicity resulltling from normal or even subtherapeutic measured concentrations. More on that in the chapter on protein binding. 10-11 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 12. Dosage Regimen (Healthy, Aged, and Diseased Patients) 10.3 Problems 10-12 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 13. Dosage Regimen (Healthy, Aged, and Diseased Patients) Alprazolam (Problem 10 - 1) Problem Submitted By: Maya Leicht AHFS 00:00.00 Problem Reviewed By: Vicki Long GPI: 0000000000 Juhl, R. et al., quot;Alprazolam pharmacokinetics in alcoholic liver diseasequot;, Journal of Clinical Pharmacology, Vol.24, (1984), p. 113 - 119. Alprazolam is an anti-anxiety agent which is metabolized to 4-hydroxy and α-hydroxy metabolites. In this study, patients with cirrhosis of the liver and healthy patients were each given doses of 1.0 mg of Alpra- zolam. The following data is for healthy patients. Alprazolam PROBLEM TABLE 10 - 1. Dose 1.0 mg BID 1.16 L/kg 1.22 529.3 AUC Assume that your patient weighs 70 kg when answering the following: 1. Find k. 2. Find the MRT. 3. Find the . 4. Find the AUMC. Find τ. 5. 6. What is N? 7. What is the patient's maximum plasma concentration, , under this dosage regimen. 8. What is the patient's average plasma concentration, , under this dosage regimen. 9. What is the patient's minimum plasma concentration, , under this dosage regimen. 10-13 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 14. Dosage Regimen (Healthy, Aged, and Diseased Patients) Cefixime (Problem 10 - 2) Problem Submitted By: Maya Leicht AHFS 00:00.00 Problem Reviewed By: Vicki Long GPI: 0000000000 Faulkner, R. et al., quot;Pharmacokinetics of cefixime after once-a-day and twice-a-day dosing to steady statequot;, Journal of Clinical Pharmacology, Vol.27, (1987), p. 807 - 812. Cefixime is a broad-spectrum cephalosporin which is active against a variety of gram positive and gram negative bac- teria. In this study, patients received a 200 mg oral dose of cefixime twice daily. Cefixime PROBLEM TABLE 10 - 2. Dose 200 mg BID 3.3 hours 286 32 AUC 14.12 1. Find k. 2. Find MRT. 3. Find Cl. 4. Find the . 5. Find the AUMC. Find τ. 6. 7. What is N? 8. What is the patient's maximum plasma concentration, , under this dosage regimen. 9. What is the patient's average plasma concentration, , under this dosage regimen. 10. What is the patient's minimum plasma concentration, , under this dosage regimen. 10-14 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 15. Dosage Regimen (Healthy, Aged, and Diseased Patients) Cefpodoxime (Problem 10 - 3) Problem Submitted By: Maya Leicht AHFS 00:00.00 Problem Reviewed By: Vicki Long GPI: 0000000000 Borin, M. et. al., quot;Pharmacokinetics and tolerance studies of cepodoxime after single-and multiple-dose oral administration of cef- podoxime proxetilquot;, Journal of Clinical Pharmacology, Vol.31, (1991), p. 1137 - 1145. Cefpodoxime proxetil is a third-generation, broad-spectrum cephalosporin which is given by the oral route. It is a pro- drug which is converted in vivo to cefpodoxime which inhibits bacterial cell wall synthesis by binding to penicillin- binding proteins. Cefpodoxime PROBLEM TABLE 10 - 3. Dose 100 mg BID 2.1 hours 271 79.1 AUC 6.9 1. Find k. 2. Find MRT. 3. Find Cl. 4. Find the . 5. Find the AUMC. Find τ. 6. 7. What is N? 8. What is the patient's maximum plasma concentration, , under this dosage regimen. 9. What is the patient's average plasma concentration, , under this dosage regimen. 10. What is the patient's minimum plasma concentration, , under this dosage regimen. 10-15 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 16. Dosage Regimen (Healthy, Aged, and Diseased Patients) Cefprozil (Problem 10 - 4) Problem Submitted By: Maya Leicht AHFS 00:00.00 Problem Reviewed By: Vicki Long GPI: 0000000000 Lode, H. et. al., quot;Multiple-dose pharmacokinetics of cefprozil and its impact on intestinal flora of volunteersquot;, Antimicrobial Agents and Chemotherapy, Vol.36, (1992), p. 144 - 149. Cefprozil is a broad-spectrum cephalosporin which is given by the oral route. In this study subjects received 500 mg doses of cefprozil every twelve hours for eight days. Cefprozil PROBLEM TABLE 10 - 4. Dose 500 mg q. 12 hours 55.11minutes 310.25 277.50 AUC 27.80 1. Find k. 2. Find MRT. 3. Find Cl. 4. Find the . 5. Find the AUMC. Find τ. 6. 7. What is N? 8. What is the patient's maximum plasma concentration, , under this dosage regimen. 9. What is the patient's average plasma concentration, , under this dosage regimen. 10. What is the patient's minimum plasma concentration, , under this dosage regimen. 10-16 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 17. Dosage Regimen (Healthy, Aged, and Diseased Patients) Clobazam (Problem 10 - 5) Problem Submitted By: Maya Leicht AHFS 00:00.00 Problem Reviewed By: Vicki Long GPI: 0000000000 Greenblatt, D. et. al., quot;Reduced single-dose clearance of clobazam in elderly men predicts increased multiple-dose accumulationquot;, Clinical Pharmacokinetics, Vol.8, (1983), p. 83 - 94. Clobazam is an agent used in the treatment of anxiety. In this study, patients received 10 mg dose of clobazam daily. PROBLEM TABLE 10 - 5. Clobazam Dose 10 mg daily 180 hours AUC 1. Find k. 2. Find MRT. 3. Find the ? 4. Find the AUMC. Find τ. 5. 6. What is N? 7. What is the patient's maximum plasma concentration, , under this dosage regimen. 8. What is the patient's average plasma concentration, , under this dosage regimen. 9. What is the patient's minimum plasma concentration, , under this dosage regimen. 10. Your patients renal function drops to 50% of normal. What would be a new dosing regimen under these condi- tions? (Assume that you want to keep < 110% of the normal and that you want to keep > 90% of the normal .) 10-17 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 18. Dosage Regimen (Healthy, Aged, and Diseased Patients) Maloprim (Problem 10 - 6) Problem Submitted By: Maya Leicht AHFS 00:00.00 Problem Reviewed By: Vicki Long GPI: 0000000000 Edstein, M., Rieckmann, K., and Veenendaal, J., quot;Multiple-dose pharmacokinetics and in vitro antimalarial activity of dapsone plus pyrimethamine (Maloprim®) in manquot;, British Journal of Clinical Pharmacokinetics, Vol.30, (1990), p.259 - 265. Maloprim is an agent which contains both dapsone and pyrimethamine. In this study, healthy volunteers were given 100 mg of dapsone plus 12.5 mg pyrimethamine weekly. The following data is for dapsone: PROBLEM TABLE 10 - 6. Maloprim Dose 100 mg weekly 22.6 hours AUC 35.0 1. Find k. 2. Find MRT. 3. Find Cl. 4. Find the . 5. Find the AUMC. Find τ. 6. 7. What is N? 8. What is the patient's maximum plasma concentration, , under this dosage regimen. 9. What is the patient's average plasma concentration, , under this dosage regimen. 10. What is the patient's minimum plasma concentration, , under this dosage regimen. 10-18 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 19. Dosage Regimen (Healthy, Aged, and Diseased Patients) Doxycycline (Problem 10 - 7) Problem Submitted By: Maya Leicht AHFS 00:00.00 Problem Reviewed By: Vicki Long GPI: 0000000000 Shmuklarsky, M. et. al., quot;Failure of doxycycline as a causal prophylactic agent against Plasmodium falciparum malaria in healthy nonimmune volunteersquot;, Annals of Internal Medicine, Vol.120, (1994), p. 294 - 298. Doxycycline is an antibiotic which has been recommended for prevention of malaria in people traveling to areas endemic to chloroquine-resistant P. falciparum malaria who are unable to take mefloquine. This study determined that doxycycline is not effective for this use. Volunteers were given 100 mg doses of doxycycline daily for 10 days. Doxycycline PROBLEM TABLE 10 - 7. Dose 100 mg daily 21.9 hours AUC 40.7 1. Find k. 2. Find MRT. 3. Find Cl. 4. Find the . 5. Find the AUMC. Find τ. 6. 7. What is N? 8. What is the patient's maximum plasma concentration, , under this dosage regimen. 9. What is the patient's average plasma concentration, , under this dosage regimen. 10. What is the patient's minimum plasma concentration, , under this dosage regimen. 10-19 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 20. Dosage Regimen (Healthy, Aged, and Diseased Patients) DQ-2556 (Problem 10 - 8) Problem Submitted By: Maya Leicht AHFS 00:00.00 Problem Reviewed By: Vicki Long GPI: 0000000000 Nakashima, M. et. al., quot;Phase I study of DQ-2556, a new parenteral 3-quaternary ammonium cephalosporin antibioticquot;, Journal of Clinical Pharmacology, Vol.33, (1993), p. 57 - 62. DQ-2556 is a new broad-spectrum cephalosporin which is active against many bacteria including Pseudomonas aerug- inosa. Subjects in this study were each given a 2000 mg infusion of DQ-2556 over 5 minutes every 12 hours for a total of 9 doses. DQ-2556 PROBLEM TABLE 10 - 8. Dose 2000 mg infusion over 5 minutes 17.6 L 8.5 7.1 AUC 241.0 1. Find Cl. 2. Find k. 3. Find the MRT. 4. Find the . 5. Find the AUMC. Find τ. 6. 7. What is N? 8. What is the patient's maximum plasma concentration, , under this dosage regimen. 9. What is the patient's average plasma concentration, , under this dosage regimen. 10. What is the patient's minimum plasma concentration, , under this dosage regimen. 10-20 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 21. Dosage Regimen (Healthy, Aged, and Diseased Patients) Erythropoetin (Problem 10 - 9) Problem Submitted By: Maya Leicht AHFS 00:00.00 Problem Reviewed By: Vicki Long GPI: 0000000000 Gladziwa, U., et al., quot;Pharmacokinetics of epoetin (recombinant human erythropoietin) after long term therapy in patients under- going haemodialysis and haemofiltrationquot;, Clinical Pharmacokinetics, Vol.8, (1983), p. 83 - 94. Erythropoetin is a regulatory hormone of red blood cells. In this study patients with end-stage renal disease were given 150 U/kg of epoetin three times a week. Glipizide PROBLEM TABLE 10 - 9. Dose 150 U/kg t.i.w. 7.7hours Cl 5.4 Assuming that your patient weighs 65 kg, please determine the following: 1. Find k. 2. Find MRT. 3. Find the . 4. Find the AUC. 5. Find the AUMC. Find τ. 6. 7. What is N? 8. What is the patient's maximum plasma concentration, , under this dosage regimen. 9. What is the patient's average plasma concentration, , under this dosage regimen. 10. What is the patient's minimum plasma concentration, , under this dosage regimen. 10-21 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 22. Dosage Regimen (Healthy, Aged, and Diseased Patients) Flecainide (Problem 10 - 10) Problem Submitted By: Maya Leicht AHFS 00:00.00 Problem Reviewed By: Vicki Long GPI: 0000000000 Forland, S. et al., quot;Flecainide pharmacokinetics after multiple-dosing in patients with impaired renal functionquot;, Journal of Clinical Pharmacology, Vol.28, (1988), p. 727 - 735. Flecainide acetate is a class 1C anti-arrhythmic agent which is used in the treatment of ventricular and supraventricular arrhythmias. In this study, subjects were given doses of 100mg of flecainide orally twice daily. PROBLEM TABLE 10 - 10. Flecainide Dose 100 mg BID 7.4 L/kg 486 89 AUC 3.429 Assume that your patient weighs 70 kg when calculating the following: 1. Find Cl. 2. Find k. 3. Find the MRT. 4. Find the . 5. Find the AUMC. Find τ. 6. 7. What is N? 8. What is the patient's maximum plasma concentration, , under this dosage regimen. 9. What is the patient's average plasma concentration, , under this dosage regimen. 10. What is the patient's minimum plasma concentration, , under this dosage regimen. 10-22 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 23. Dosage Regimen (Healthy, Aged, and Diseased Patients) Glipizide (Problem 10 - 11) Problem Submitted By: Maya Leicht AHFS 00:00.00 Problem Reviewed By: Vicki Long GPI: 0000000000 Kradjan, W. et al., quot;Glipizide pharmacokinetics: effects of age, diabetes, and multiple dosingquot;, Journal of Clinical Pharmacology, Vol.29, (1989), p. 1121 - 1127. Glipizide is a second-generation oral hypoglycemic agent used in the treatment of non-insulin-dependent (type II) dia- betes. In this study, both diabetic and non-diabetic elderly men were each given doses of 2.5 mg of glipizide daily for five days. The data for the non-diabetic group is given below. PROBLEM TABLE 10 - 11. Dose 2.5 mg daily 4.0 hours 0.47 AUC 2325.4 1. Find k. 2. Find MRT. 3. Find Cl. 4. Find the . 5. Find the AUMC. Find τ. 6. 7. What is N? 8. What is the patient's maximum plasma concentration, , under this dosage regimen. 9. What is the patient's average plasma concentration, , under this dosage regimen. 10. What is the patient's minimum plasma concentration, , under this dosage regimen. 10-23 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 24. Dosage Regimen (Healthy, Aged, and Diseased Patients) Lomefloxacin (Problem 10 - 12) Problem Submitted By: Maya Leicht AHFS 00:00.00 Problem Reviewed By: Vicki Long GPI: 0000000000 Hunt, T. and Adams, M., quot;Pharmacokinetics and safety of lomefloxacin following multiple dosesquot;, Diagn Microbiol Infect Dis, Vol.12, (1989), p. 181 - 187. Lomefloxacin is a quinolone antibiotic which is useful against both Gram-positive and Gram-negative bacteria. It is used in the treatment of urinary tract infections and lower respiratory tract infections. A dose of 400 mg of lomefloxa- cin was given twice daily to healthy patients. PROBLEM TABLE 10 - 12. Lomefloxacin Dose 400 mg BID 7.32 hours AUC 61.67 1. Find k. 2. Find MRT. 3. Find Cl. 4. Find the . 5. Find the AUMC. Find τ. 6. 7. What is N? 8. What is the patient's maximum plasma concentration, , under this dosage regimen. 9. What is the patient's average plasma concentration, , under this dosage regimen. 10. What is the patient's minimum plasma concentration, , under this dosage regimen. 10-24 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 25. Dosage Regimen (Healthy, Aged, and Diseased Patients) Loratadine (Problem 10 - 13) Problem Submitted By: Maya Leicht AHFS 00:00.00 Problem Reviewed By: Vicki Long GPI: 0000000000 Radwanski, E. et al., quot;Loratadine: multiple-dose pharmacokineticsquot;, Journal of Clinical Pharmacology, Vol.27, (1987), p. 530 - 533. Loratadine is an antihistamine which is orally active. In this study, healthy, male volunteers were each given a 40-mg loratadine capsule daily for ten days. PROBLEM TABLE 10 - 13. Loratadine Dose 40 mg daily 14.4 hours AUC 96.0 1. Find k. 2. Find MRT. 3. Find Cl. 4. Find the . 5. Find the AUMC. Find τ. 6. 7. What is N? 8. What is the patient's maximum plasma concentration, , under this dosage regimen. 9. What is the patient's average plasma concentration, , under this dosage regimen. 10. What is the patient's minimum plasma concentration, , under this dosage regimen. 10-25 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 26. Dosage Regimen (Healthy, Aged, and Diseased Patients) Methamphetamine (Problem 10 - 14) Problem Submitted By: Maya Leicht AHFS 00:00.00 Problem Reviewed By: Vicki Long GPI: 0000000000 Cook, C., et al., quot;Pharmacokinetics of oral methamphetamine and effects of repeated daily dosing in humansquot;, Drug Metabolism and Disposition, Vol.20, (1992), p. 856 - 861. Methamphetamine is a CNS stimulant which is used in the treatment of attention deficit disorder and obesity. In this study, subjects were given a 0.125 mg/kg dose of methamphetamine daily. PROBLEM TABLE 10 - 14. Methamphetamine Dose 0.125 mg/kg daily 8.46 hours 65.0 212 Assume that your patient weighs 70 kg when calculating the following: 1. Find k. 2. Find MRT. 3. Find the . 4. Find the AUC. 5. Find the AUMC. Find τ. 6. 7. What is N? 8. What is the patient's maximum plasma concentration, , under this dosage regimen. 9. What is the patient's average plasma concentration, , under this dosage regimen. 10. What is the patient's minimum plasma concentration, , under this dosage regimen. 10-26 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 27. Dosage Regimen (Healthy, Aged, and Diseased Patients) Mexiletine (Problem 10 - 15) Problem Submitted By: Maya Leicht AHFS 00:00.00 Problem Reviewed By: Vicki Long GPI: 0000000000 Gillis, A. and Kates, R., quot;Clinical pharmacokinetics of the newer antiarrhythmic agentsquot;, Clinical Pharmacokinetics, Vol.9, (1984), p. 375 - 403. Mexiletine is a class Ib antiarrhythmic agent. In this study, volunteers each received a 1600 mg dose orally each day. PROBLEM TABLE 10 - 15. Mexiletine Dose 1600 mg daily 380 L 681 1. Find k. 2. Find the MRT. 3. Find the . 4. Find the AUC. 5. Find the AUMC. Find τ. 6. 7. What is N? 8. What is the patient's maximum plasma concentration, , under this dosage regimen. 9. What is the patient's average plasma concentration, , under this dosage regimen. 10. What is the patient's minimum plasma concentration, , under this dosage regimen. 10-27 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 28. Dosage Regimen (Healthy, Aged, and Diseased Patients) Moxisylyte (Problem 10 - 16) Problem Submitted By: Maya Leicht AHFS 00:00.00 Problem Reviewed By: Vicki Long GPI: 0000000000 Costa, P. et al., quot;Multiple-dose pharmacokinetics of moxisylyte after oral administration to healthy volunteersquot;, Journal of Phar- maceutical Sciences, Vol.82, (1993), p. 968 - 971. Moxisylyte is an α-adrenergic blocker which has been used in Europe for some times as a vasodilator in the treatment of such disease states as age-associated mental impairment, acrocyanosis, Raynaud's syn- drome, vascular cochlearvestibular disorders, glaucoma, and benign prostatic hyperplasia. PROBLEM TABLE 10 - 16. Moxisylyte Dose 240 mg BID 2.28 hours AUC 11186 1. Find k. 2. Find MRT. 3. Find Cl. 4. Find the . 5. Find the AUMC. Find τ. 6. 7. What is N? 8. What is the patient's maximum plasma concentration, , under this dosage regimen. 9. What is the patient's average plasma concentration, , under this dosage regimen. 10. What is the patient's minimum plasma concentration, , under this dosage regimen. 10-28 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 29. Dosage Regimen (Healthy, Aged, and Diseased Patients) Naproxen (Problem 10 - 17) Problem Submitted By: Maya Leicht AHFS 00:00.00 Problem Reviewed By: Vicki Long GPI: 0000000000 Ouweland, F. et. al., quot;Hypoalbuminaemia and naproxen pharmacokinetics in a patient with rheumatoid arthritisquot;, Clinical Phar- macokinetics, Vol.11, (1986), p. 511 - 515. The pharmacokinetics parameters of naproxen were looked at in patients with rheumatoid arthritis in this study. A patient received a dose of 500 mg of naproxen orally twice daily. PROBLEM TABLE 10 - 17. Naproxen Dose 500 mg BID 9.0 L AUC 1134 1. Find Cl. 2. Find k. 3. Find the MRT. 4. Find the . 5. Find the AUMC. Find τ. 6. 7. What is N? 8. What is the patient's maximum plasma concentration, , under this dosage regimen. 9. What is the patient's average plasma concentration, , under this dosage regimen. 10. What is the patient's minimum plasma concentration, , under this dosage regimen. 10-29 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 30. Dosage Regimen (Healthy, Aged, and Diseased Patients) Nisoldipine (Problem 10 - 18) Problem Submitted By: Maya Leicht AHFS 00:00.00 Problem Reviewed By: Vicki Long GPI: 0000000000 Harten, J. et al., quot;Influence of renal function on the pharmacokinetics and cardiovascular effects of nisoldipine after single and multiple dosingquot;, Clinical Pharmacokinetics, Vol.16, (1989), p. 55 - 64. Nisoldipine is a second-generation calcium-channel blocker which is under investigation for use as an anti-hyperten- sive agent. Nisoldipine is mainly eliminated through liver metabolism with metabolites being excreted mainly in the urine but also in the feces. The systemic clearance of nisoldipine depends greatly on liver blood flow. PROBLEM TABLE 10 - 18. Nisoldipine Dose 10 mg BID orally 7.9 hours AUC 5.2 1. Find k. 2. Find MRT. 3. Find Cl. 4. Find the ? 5. Find the AUMC. Find τ. 6. 7. What is N? 8. What is the patient's maximum plasma concentration, , under this dosage regimen. 9. What is the patient's average plasma concentration, , under this dosage regimen. 10. What is the patient's minimum plasma concentration, , under this dosage regimen. 10-30 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 31. Dosage Regimen (Healthy, Aged, and Diseased Patients) Pefloxacin (Problem 10 - 19) Problem Submitted By: Maya Leicht AHFS 00:00.00 Problem Reviewed By: Vicki Long GPI: 0000000000 Bruno, D. et al., quot;Bayesian versus NONMEM estimationquot;, , Vol. , (19 ), p. 657 - 668. Pefloxacin is an antibiotic used to treat patients who are in the intensive care unit. For this study, patients were given a 400 mg dose of pefloxacin twice daily for eight days. PROBLEM TABLE 10 - 19. Pefloxacin Dose 400 mg BID 21.3 hours Cl 3.77 1. Find k. 2. Find MRT. 3. Find the ? 4. Find the AUC. 5. Find the AUMC. Find τ. 6. 7. What is N? 8. What is the patient's maximum plasma concentration, , under this dosage regimen. 9. What is the patient's average plasma concentration, , under this dosage regimen. 10. What is the patient's minimum plasma concentration, , under this dosage regimen. 10-31 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
- 32. Dosage Regimen (Healthy, Aged, and Diseased Patients) Phenylpropanolamine (Problem 10 - 20) Problem Submitted By: Maya Leicht AHFS 00:00.00 Problem Reviewed By: Vicki Long GPI: 0000000000 Scherzinger, S., Rowse, R., and Kanfer, I., quot;Steady state pharmacokinetics and dose-proportionality of phenylpropanolamine in healthy subjectsquot;, Journal of Clinical Pharmacology, Vol.30, (1990), p. 372 - 377. Phenylpropanolamine is a sympathomimetic agent which is used both for its action as a nasal decongestant and its action as an anorexiant. In this study healthy volunteers were given doses of 25 mg every four hours for a total of seven doses. It was found that phenylpropanolamine is 77% renally excreted. PROBLEM TABLE 10 - 20. Phenylpropanolamine Dose 25 mg q. 4 hours 4.71 hours 4.08 L/kg 0.5 1. Find k. 2. Find MRT. 3. Find Cl. 4. Find the AUC. 5. Find the AUMC. Find τ. 6. 7. What is N? 8. What is the patient's maximum plasma concentration, , under this dosage regimen. 9. What is the patient's average plasma concentration, , under this dosage regimen. 10. What is the patient's minimum plasma concentration, , under this dosage regimen. 10-32 Basic Pharmacokinetics REV. 99.4.25 Copyright © 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/

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