introduction - basic pharmakokinectics

CHAPTER 1 Introduction

Author: Michael Makoid and John CobbyReviewer: Phillip Vuchetich

OBJECTIVES

At the completion of this chapter, the successful student shall be able to:

1. define pharmacokinetics

2. state the overall objectives of the course

3. state the major themes of the course

4. state the course organizational structure with respect to study sections

5. state the objectives of each study section

6. state the examination structure and objectives

7. state student performance expectations

8. state the schedule and timeline

Basic Pharmacokinetics REV. 00.1.11 1-1Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf/

Introduction

1.1 Basic Pharmacokinetics

What is pharmacokinet-ics?

Pharmacokinetics is the mathematics of the time course of Absorption, Distribu-tion, Metabolism, and Excretion (ADME) of drugs in the body. The biological, physiological, and physicochemical factors which influence the transfer processes of drugs in the body also influence the rate and extent of ADME of those drugs in the body. In many cases, pharmacological action, as well as toxicological action, is related to plasma concentration of drugs. Consequently, through the study of pharmacokinetics, the pharmacist will be able to individualize therapy for the patient.

Basic Pharmacokinetics REV. 00.1.11 1-2Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf

Introduction

1.2 Course Objectives:

The Roman numerals refer to the cognitive complexity as described in Bloom’s Taxonomy of Educational Objectives described elsewhere in this document. At the completion of this course, the successful student will be able to:

What will you be able to do?

• Calculate (III) patient and drug specific pharmacokinetic parameters from patient data,

• Predict (calculate - III) the changes in relevant pharmacokinetic parameters in the patient with selected diseases,

• Utilize the above parameters to individualize patient therapy (devise a dosage regimen - V),

• Communicate his/her therapy recommendations to another competent health professional (write a consult - V).

1.2.1 COURSE ARRANGEMENT:

Two courses are described below. The first, a two credit (Creighton University required) and the second, a three credit (CU optional) version. The two credit course will consist of major themes one through three and exams one and two, while the three credit course will add theme four and exam three. The four major themes are entitled:

How is the course arranged?

• Study Group 1: Learn the tools used by the discipline. Calculate patient and drug specific phar-macokinetic parameters from single dose patient data,

• Study Group 2: Utilize the tools to optimize patient therapy under multiple dose conditions,

• Study group 3: Apply the tools to predict the changes in relevant pharmacokinetic parameters in the compromised patient patient with selected diseases,

• Study group 4: Apply the tools in specialized drug classes.

Each major theme of the course is further broken down into study sections, eachwith their own set of general objectives as shown below:


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1.2.2 STUDY GROUP 1: LEARN THE TOOLS USED BY THE DISCIPLINE. CALCULATE PATIENT AND DRUG SPECIFIC PHARMACOKINETIC PARAMETERS FROM SINGLE DOSE PATIENT DATA,

A. Basic Mathematical skills objectives:What will I be required to be able to do? How will examination ques-tions be written for this material?

1. Given a data set containing a pair of variables, the student will properly construct (III) var-ious graphs of the data.

2. Given various graphical representations of data, the student will calculate (III) the slope and intercept by hand as well as using linear regression.

3. The student shall be able to interpret (V) the meaning of the slope and intercept for the various types of data sets.

4. The student shall demonstrate (III) the proper procedures of mathematical and algebraic manipulations.

5. The student shall demonstrate (III) the proper calculus procedures of integration and dif-ferentiation.

6. The student shall demonstrate (III) the proper use of computers in graphical simulations and problem solving.

7. Given the assumptions for the model, the student will construct (III) models of the ADME processes using Laplace Transforms.

8. The student shall develop (V) integrated equations associated with the above models.9. The student shall generate a pharmacokinetic model based on given information.10. The student shall interpret a given model mathematically.11. The student shall predict changes in the final result based on changes in variables through-

out the model.

B. Pharmacological Response objectives: 1. Given patient data of the following types, the student will be able to properly construct

(III) a graph and compute (III) the slope: response (R) vs. concentration (C), response (R) vs. time (T), concentration (C) vs. time (T)

2. Given any two of the above data sets, the student will be able to compute (III) the slope of the third.

C. IV one compartment model, plasma and urine objectives:1. Given patient drug concentration and/or amount vs. time profiles, the student will calcu-

late (III) the relevant pharmacokinetic parameters available ( , K, , , , Clear-

ance, MRT) from IV data.2. Given the appropriate pharmacokinetic parameters, the student shall simulate (III)

I.V. bolus/infusion dosing for parent compounds

Plasma concentration vs. time profile analysis

Rate vs. time profile analysis3. Given patient specific pharmacokinetic parameters, the student shall provide professional

communication regarding IV bolus/infusion information4. The student shall utilize computer aided instruction and simulation5. Given patient drug concentration and/or amount vs. time profiles, the student will calcu-

late (III) the relevant metabolite (active vs. inactive) pharmacokinetic parameters avail-able ( , K, , , , Clearance, MRT) from IV data.

Vd km kr AUC

Vd km kr AUC


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D. Biopharmaceutical factor objectives: the student shall be able to discuss:1. physiology and mechanisms of absorption2. effects of diffusion, cardiac output / blood perfusion, physical properties of the drug and

body on distribution3. biotransformation, first pass effect, and clearance4. renal, biliary, mammary, salivary, other forms of excretion.5. the effects of physiological changes with age, sex, and disease on the absorption, distribu-

tion, metabolism, and excretion of a drug.

E. Oral one compartment model objectives:1. Given patient drug concentration and/or amount vs. Time profiles, the student will calcu-

late (III) the relevant pharmacokinetic parameters ( , K, , , , , Clearance,

MRT, MAT) available from oral data.

F. Bioavailability objectives:1. Given sufficient data to compare an oral product with another oral product or an IV prod-

uct, the student will estimate (III) the bioavailability (compare AUCs) and judge (VI) pro-fessional acceptance of the product with regard to bioequivalence (evaluate (VI) AUC,

and ).

2. The student will write (V) a professional consult using the above calculations.

1.2.3 STUDY GROUP 2: UTILIZE THE TOOLS TO OPTIMIZE PATIENT THERAPY UNDER MULTIPLE DOSE CONDITIONS,

G. Dosage regimens objectives:1. Given population average patient data, the student will devise (V) dosage regimens which

will maintain plasma concentrations of drug within the therapeutic range.2. Given specific patient information, the patient will justify (VI) dosage regimen recom-

mendations.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

1.2.4 STUDY GROUP 3: APPLY THE TOOLS TO PREDICT THE CHANGES IN RELEVANT PHARMACOKINETIC PARAMETERS IN THE COMPROMISED PATIENT PATIENT WITH SELECTED DISEASES,

H. Clearance objectives:1. Given patient information regarding organ function, the student will calculate (III)

changes in clearance and other pharmacokinetic parameters inherent in compromised patients.

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1.2.5 STUDY GROUP 4: APPLY THE TOOLS IN SPECIALIZED DRUG CLASSES.

I. Two Compartment Model objectives:1. Given patient Concentration and/or Amount of Drug vs. Time, profiles the student will

calculate (III) the relevant pharmacokinetic parameters( , Alpha, , Beta, ,

, , , , Clearance, compartmental amount ratios) available from two com-

partment data.2. Given population average patient data, the student will devise (V) a dosage regimen which

will maintain plasma concentrations of drug within the therapeutic range.3. Given specific patient information, the patient will justify (VI) the optimal dosage regi-

men.4. Given patient information regarding organ function, the student will devise (V) and justify

(VI) the optimal dosage regimen for the compromised patient.5. The student will write (V) a professional consult using the above calculations.

J. Non-linear kinetics objective:1. Given population average patient data, the student will devise (V) a dosage regimen which

will maintain plasma concentrations of drug within the therapeutic range.2. Given specific patient information, the patient will justify (VI) the optimal dosage regi-

men.3. Given patient information regarding organ function, the student will devise (V) and justify

(VI) dosage regimens for the compromised patient.4. The student will write (V) a professional consult using the above calculations.

Vd1 A1 B1

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Introduction

1.3 Exams

How are the exams made?

Exams will consist of problems which will be linked directly back to an objective(above) and a library assignment in which you will be asked to evaluate a researcharticle with the tools available to you by the time of the exam as discussed below.


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1.3.1 LIBRARY ASSIGNMENT IN PHARMACOKINETICS

K. Library Assignment ObjectivesWhat do I have to do in the library?

1. Given a suitable primary research article in the area of pharmacokinetics, the student shall calculate the pharmacokinetic parameters from the data using the tools learned in class both by hand and utilizing the computer program, PK Solutions.

2. The student shall communicate in writing the results of such calculations with suitable commentary regarding differences and interpretations.

Format of the “paper”:

How should the paper look?

1. Tell me what type of paper you have chosen to evaluate:

The problem sets show what data you need for each of these.

First Exam

What content should I look for in the paper and what is its relative worth?

IV Bolus Parent compound 50 pts

IV Bolus Parent metabolite 65 pts

IV Infusion 65 pts

Pharmacological Response 75 pts

Oral Dosing / Bioavailability 50 pts

Second Exam (Pharm.D. course)

Multiple dosing 50 pts

Clearance and disease 60 pts

Dosage Regimen 75 pts

Third Exam (Masters / Honors course)

Two compartment model 50 pts

Protein Binding and Disease 65 pts

Non-linear kinetics and disease 75 pts

2. Include a Xerox copy of the entire paper. I need to evaluate it, too.

3. Enlarge the graph by successive Xeroxes so that you can accurately ate the data.

4. Do analysis of data by hand and by PK Solutions.

5. Compare your work with the author’s (short paragraph).


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6. Comment on any differences of parameter calculation or interpretation. Seeobjectives above (Paragraph).

7. Write an exam question to obtain pharmacokinetic parameters. You knowfrom the first exam what they should look like.

Why do I need to do this library assignment?

Each of the above sections is designed to bring the student an understanding of theinformation and the processes necessary to operate as a competent professional inthe area of pharmacokinetic evaluation and consulting. Consequently, thecourse will evolve from a quantitative, manipulative mathematics course to acourse which stresses communication skills. Consults will be graded not only oncontent (the proper dosage regimen for the patient) but also grammar, punctuation,spelling, organization and neatness. You may have the best medical information inthe world, but if it is poorly executed, it will be ignored.

Can I cram the night before?

This course will probably be one of the more rigorous ones that you will haveexperienced in your college career to date. It will be one of the first ones whichattempt to show some clinical relevance. The course can be successfully com-pleted with your current skills and background. It is not difficult IF (and that is abig IF) taken slowly, in small bites. Its just like eating an elephant - you can’t do itall in one sitting. Some of you may try to get it all the night before the exam,regardless of my admonitions and those of your upper-class friends (ask them!). Inmany cases, that has been more than sufficient to get A’s and B’s on exams in pre-vious courses. Past experience tells many of you that you can do it. I suggest thatthe requirements and expectations of a professional school are considerably morethan your undergraduate experience and it most likely will not work in manycourses which require assimilation of the information presented, as is expected in aprofessional program.


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1.4 Blooms taxonomy for the Hierarchy of Educational Objectives

Blooms taxonomy for the Hierarchy of Educational Objectives describes the expectations of a course in increasing order of complexity as:

What is cramming good for? Lowest level of cog-nitive skills.

I. To Know: means to memorize (recognize, recall) (Many college coursesrequire only this level of cognitive effort, hence the extensive experience with“multiple guess” exams).

II. To Comprehend: means to translate; to be able to put information into own words. (Essay exams routinely call for this level of effort on the part ofstudent).

This is where we begin. III. To Apply: means to be able to use knowledge, rules and principles iunfamiliar situation. (This is the lowest level of skill necessary to function technician level).

This is where we need to be in school.

IV. To Analyze: means to be able to critically examine a body of knowleand to be able to identify the relationships. (This is where a B.S. graduate soperate. Education obviates the need for teachers.)

This is where we need to be as graduates.

V. To Synthesize: means to put together information, not necessarily pously so organized, in order to get a new piece of information. (This is the bning level of professional judgment).

VI. To Evaluate: means to be able to judge the worth of an idea, form hyposes and do problem solving, research, invent new knowledge. (This is the dolevel of participation in the area).

Can’t I just do it the same way that I have always studied?

A professional routinely operates at level IV and V with occasional forays intolevel VI. This is where you will operate in this course and in most subsequentcourses in the professional curriculum. You will note that each of the objectives forthe course contains specific action words followed by the level in the taxonomy atwhich you will operate. These are the standard descriptive terms for use in instruc-tional objectives. You will be asked to do critical thinking, not simply recite orrecognize the right answer. Problems challenge thinking skills and demand thesynthesis of material into concepts. To facilitate this transition we both must workvery hard.


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1.5 Course Contract

I Will:

What will the teacher do in this class? Act as a facilitator.

1. Provide individualized learning methods: Some students learn by hearingand others by seeing (auditory or visual learners). I have designed the course toaccommodate both types of learners. In class, I will provide you with executivesummaries of what you read. I will provide group leaders with detailed reviews ofmaterials for which they are responsible. I will tell you what I’m going to say, sayit, and then tell you what I said. I will also attempt to write it out and draw appro-priate graphs, charts and pictures as well as appropriate visual aids in class andwith the homework problems. I will provide you with ample examples of the typesof manipulations that you will be expected to do. I will provide you with ampleproblem sets so that you may practice those manipulations. I will provide youwith computer simulations so that you may see these manipulations in action andbegin to get a feel for the numbers and their magnitude. Feedback and interactionis encouraged. If I am not meeting your perceived needs, you must tell me. Somestudents might feel too intimidated to ask questions. To obviate this problem, youwill elect a group team leader, an ombudsman, whose job it will be to carry yourquestions, concerns, and comments to me. It is your job and his responsibility tosee that the group interaction facilitates the learning process. This is not to preventyou coming to see me but offered as another avenue of communication.

Will I learn anything rel-evant in this course?

2. Provide clinical relevance to the practice of pharmacy. This will be stressedat all times. I will also relate real clinical experiences; virtually all of the problemscome from real patients. Some educators believe examples must fit the theoryexactly. This gives the student a false set of reality parameters. Consequently,when “the data does not fall on the line” the student rejects relevant informaYou will become familiar with real data, and the problems associated withdata.

How will I know how I’m doing?

3. Give adequate feedback: Evaluation of your performance will be availableto you at all times. A running evaluation, updated weekly will be on my door foryour review. You may check any thing with me at any time. I expect that you willsee me outside of class time either individually if you need help or in supervisedreview sessions. You must see me for assistance if your performance is unsatis-factory.

What will the teacher be doing? Engaging you in an active learning pro-cess.

4. Teach: As an operational definition this means: clarifying what you read,demonstrating how and why things work as they do, and unifying the material -attempting to generate the A - HA! syndrome. The correlate of teach from the stu-dent view is learn. Neither is a passive process. I can not open your head and pourthe knowledge in. A saying in education is: “Knowledge maketh a bloentrance”. You must expend the effort necessary for you to learn.


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What must I do in this active learning process? You MUST participate in class and in your assigned groups!!!

5. Facilitate Learning. You received objectives (above) and a summary foreach study section (chapters in this text), of exactly what is expected of you withexamples in the problem sets at the end of each chapter. We will have ample timeduring class to field questions generated by the correlated reading and problemsets, as well as homework assignments. I will not be duplicating any book’s efforts.Student participation in class is required. You will answer (as well as ask) ques-tions, do problems in class. You will sound things out and get feedback from meand your fellow colleagues. Remember - the class is to help you learn. It is not thesole means of learning, nor am I the source of all knowledge. Its’ only reasobeing is to help you organize and summarize what you learn. It has a relasimple plan with multiple examples. From these examples you will develop cepts which will obviate the need for memorizing individual facts (or actuallyentirely). I will assist you in the formation of these concepts. It is patently obvthat I can not give you every possible example of every type of question thawill be asked during your professional career. For one thing I don't know wquestions you will be asked nor problems you will encounter. Going from thecific to the general forms concepts which will allow you to go from the generathe specific, even if you have never been there before. The total medical kedge is now doubling at a rate of every 4 years. I can not teach you the conteessary to operate 5 years in the future, let alone 40. You must learn to learn.Hence, if you plan to become a competent professional, you must operate ain Bloom's level V.

How do I get in touch with the teacher?

6. Be available: I do not have office hours. I believe them to be restricfrom your view point. What I do have is a schedule calandar preparede weeadvance of when I am NOT available. You may set an appointment, at leastday in advance to guarantee that I see it, any other time. Of course, appointare not necessary if I'm in my office, but you take the chance of my not being or someone else being there ahead of you if you do not sign up. You may cme by e-mail: [email protected], or by phone: 402-280-2952. You may contact my secretary, Dawn Trojanowski in the departmental office or by ph402-280-2893 to make an appointment.

How can I tell the teacher how things are going?

7. Be responsive: Each day, you will be asked to provide me with aminute summary of the topic consisting answering the following questions:

a. What was the main thrust of the study section (What did you re

b. What was clear about the study section? What was done well?

c. What was unclear? How could it be done better?

This will provide me with a running monitor of my effectiveness as well aframework of what to stress and what to change.


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Do I have any say in the examination questions?

After each exam, in addition to working out the problems, we will decide whetherany individual question was not covered by the objectives. Note: Not that it wastough, not that you got it wrong, not that it didn’t allow you to tell me what youknew, but did I tell you that I was going to ask you to do it? (Was it covered by theobjectives?)

How are the exams graded?

8) Evaluate your performance fairly and honestly: Quite simply, I’m going to tellyou what I expect that you will do. I will show you how to do it. I will provide youwith practice in doing it. I will provide you with an exam which tests your abilityto do it. The exams, as well as the whole course, will use real data and/or pharma-cokinetic parameters for real drugs in real patient settings, much like the stateboard exams (and hopefully real life). Like both of these situations, all answers areinterconnected. What that means is, if you improperly calculate a parameter whichis needed to make another calculation which is used to make a third, etc. ALL arewrong. Conversely, if you can’t get a particular calculation by one method or equa-tion, try another. That’s simply the way it is. You probably wouldn’t get much sym-pathy if you calculated a dosage regimen properly based on a wrong eliminationrate constant and ended up killing your patient.

You Will:

What do I have to do? How much work is really expected?

1) Come prepared to participate in class. This is your full time job. If you areworking full time, it is usually 40 to 60 hours per week. If you go to college 15 to18 credits and prepare/study 2 hours for each credit, you work 45 to 55 hour perweek - you have a full time job. Your commitment is the 45 to 50 hour week notjust the contact hours and a night for each exam. This specifically means for each 1hour class, I expect no less than 2 hours of preparation on your part. Each of youwill be assigned to a study group. You will work the problems together and teacheach other both in and out of class. We will have group discussion of class as wellas group problem solving. It will be your responsibility that every member ofyour group be adequately prepared to answer for the group during recitation. Therewill be a grade for group participation. Part of your grade will be based on yourpeer evaluation.

Do I have to read the text?

2) Read the text. When you read, read critically. Do you understand each idea?Each page in the HTML version has an evaluation section. If you get it you will beasked to be a resource for that page for your peers. If you don’t get it, you will bedirected to your peers to seek help. Come prepared to ask about it in class.

Why do I have to do the problem sets?

3) Work the problems. Check the answers. These come from old exams, so theyare the type that you are likely to see. Work them in your study groups so thateveryone can see your thought processes. Bring them to class if you can not dothem or come and see me privately. Be prepared to show me your attempts at solv-ing the problem. I will show you how to get started and give direction to yourthought. I will not work the problem for you. You would not learn if I did it foryou. It is crucial that you work the problems. Each has a specific objective. Over-


Introduction

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all, they contribute to your gaining facility in the processes that a pharmacokineti-cist must know how to do.

Can I just coast through?

4) Do not delude yourself with respect to your performance. If you received agrade that was less than satisfactory for you, do not simply console yourself bysaying “I knew the stuff, I just made a little error.” Can you get it right contently? That's when you know the stuff. That is not a laudable goal. That's wprofessional does. There have been several students in the past that “knestuff” right up till the time that they had to repeat the course (and sometbeyond).


Introduction

1.6 Computers in the course

Can I get through with just paper and pencil?

Computer literacy is necessary in this field. Consequently computers will pervadethe course. The homework problems (above) are to done both by hand andchecked with the computer. This will help your understanding of pharmacokineticsin general and that homework objective in particular. Computers are naturaladjunctive tools in the teaching of pharmacokinetics. The are able to simulate theconcentration vs. time profiles and do difficult repetitive calculations which allowthe student to get a broad view of the processes involved.

What are the programs that I will be using?

Program that is becomming the industry standard and is currently being used in thecourse is PK Solutions. We have a site licence for it and a working copy is in thecomputer lab. It is a required text for the course. You will need to learn to use thesoftware as complete instructions are available with its purchase.

In addition to the above course objectives, there are specific objectives for the useof computers in the course. They are:

What will I be expected to do with the comput-ers?

• Simulation. The student will be able to utilize appropriate graphs and histograms used classical pharmacokinetics in the course. The student will demonstrate effects of changes in pharmacoki-netic parameters on the ADME processes and correlated pharmacological / therapeutic response.

• Graphical Solutions. Many thing become more understandable in graphical form, or at least we are able to predict what would happen if a trend were to continue.

• Numerical solutions. The computer would accurately and repeatedly calculate convoluted, diffi-cult equations quickly and easily.

These objectives will be met in a variety of ways. Clearly, the most direct methodis the solution of the problem sets by computer. First, I expect that you would dothe problem by hand, complete with graphs and other supporting calculations fol-lowed by computer simulation and data analysis. Just how close did you come tothe best fit? Next, a portion of each exam will be a library exercise in which youwill find and evaluate a published article according to the principles that youlearned in class utilizing the computer facilities. How close did you come theauthors numbers? Do you, in fact, even agree with the authors? You will prepare ashort consult in which you describe the patient and what the authors did along withyour support (or non-support) of the authors conclusions.


Introduction

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1.7 Survival Kit

1.7.1 THINGS FOR YOUR SURVIVAL KIT!

What do I need to buy RIGHT NOW?

1. You will need a good calculator - One with and functions. You musthave it ASAP. You will use it in class.

2. You will also need 2 cycle semilog paper and a clear straight edge ruler foruse in class. These are available in the book store or at an office supply store. Youcan also downoad a copy of graph paper printer for you own personal use. A copyis available in the computer lab.

3. You will need access to a pentium computer. The software, PK Solutions,is pre-loaded in the Criss computer lab. Purchase is required for home use.

4. You will need a 3” D three-ring binder for collecting and maintaining the pages in this book as well as your class notes.

What do I need to do in and out of class?

Work in your study groups. You never learn it so well as when you teach someone else. Everyone benefits from a well run prepared study group. Yonot in competition with your fellow classmates. If everyone earns an “A”, teveryone will receive one.

How can I organize this material?

Organize and label your study notes. This is basic survival. This is one strthat I find works well. I recommend it highly. Good study notes are formattedloose-leaf in a three ring binder. The individual pages have a line drawn dabout 1/3 the way in. The notes are taken on the right (2/3) of the page, labels go in the left. The labels on the left are often written as questions, whicanswered in the text on the right. Loose leaf binders allow for the incorporatioreading summaries as well as relevant problems and homework to be orgawith a divider all in one place. You should write intelligently, with proper puncttion and spelling as if you were preparing a consult for a physician. Organizatthe key.

Remember: you may have all the information in the world at your fingertipsable to solve the most difficult therapy problem and no one will listen to you if can't communicate intelligently. You will be required to communicate in course utilizing both written and verbal skills.

Chapters in the book will be organized as above.

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1.7.2 WHAT YOU WILL GAIN: (YOUR GOALS)

How is the course to be graded?

1. At the lowest level, a decent grade for a significant course. Specific gradeswill be earned by attaining the following points:

• A 900 and above

• B+ 850 to 899

• B 800 to 849

• C+ 750 to 799

• C 700 to 749

• D 600 to 699

• F 599 and below

Points in the course are assigned for various activities:

You will be require to pass the first exam before you are allowed to take thesecond.

2. At the next higher level, I will guarantee that if you comprehend this mate-rial at level V, you will have no trouble passing any state board anywhere withregard to pharmacokinetics.

3. You will gain a useful skill that will make you an integral part of the healthcare team.

Do I really need a teacher to learn?

4 You will learn to learn. There is an old proverb which goes: “Give a mafish and you feed him for a day. Teach a man to fish and you feed him for atime.” The B.S. Degree is designed to eliminate teachers. An educated man who has learned to how to learn, not one who memorized a page in a book. is what you need to be a professional. The total medical knowledge is doublinrate of every 3-4 years. That means that you will be out of date shortly after gation (if not before) if you simply memorized content and don't learn to learncontinue to learn throughout your career.

TABLE 4-1

Exam 1 410

Exam 1 grp/ind 40

Library 1 50-75

Exam 2 410

Exam 2 grp/ind 40

Library 2 50 to 75

Total 1000 to 1050

Group Bonus -50 to +50

Group Total 950 to 1100


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What about cheating? One last piece of information: Neither you nor I will not tolerate any academicmisconduct. Anyone caught will minimally receive an “F” for their efforts anwill recommend dismissal from the program. The profession has no roomunprofessional behavior. I will prosecute.


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1.8 Tentative Schedule

1.8.1 STUDY GROUP 1: LEARN THE TOOLS USED BY THE DISCIPLINE. CALCULATE PATIENT AND DRUG SPECIFIC PHARMACOKINETIC PARAMETERS FROM SINGLE DOSE PATIENT DATA,

A: Introduction1. Texts2. Literature3. Grading Policy4. Course Philosophy

B: Math review1. Numbers and exponents 2. Graphs and reaction order3. Calculus4. Laplace transform 5. Computer Introduction6. Computer simulation and problem sets

C: Pharmacokinetic modeling1. What a model is and what it isn’t.2. Why we model3. Philosophy of modeling

D: Pharmacological Response1. Michaelis - Menton Mass balance equation2. Interrelationships between Concentration, time and response.

E: I.V. Bolus dosing1. Parent compound

I. Plasmaa. Plasma concentration vs. time profile analysisb. Computer aided instruction and simulationc. Problem setsd. Professional communication.

II Urinea. Amount vs. time profile analysisb. Rate vs. time profile analysisc. Computer aided instruction and simulation d. Problem sets


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e. Professional communication. 2. Metabolite

I. Plasmaa. Plasma concentration vs. time profile analysisb. Computer aided instruction and simulation c. Problem sets d. Professional communication.

II. Urine a. Rate vs. time profile analysis b. Computer aided instruction and simulation c. Problem sets d. Professional communication.

F: I.V. infusion1. Parent compound

I. Plasma a. Plasma concentration vs. time profile analysisb. Computer aided instruction and simulation c. Problem sets d. Professional communication.

II. Urine a. Amount vs. time profile analysisb. Rate vs. time profile analysis c. Computer aided instruction and simulation d. Problem sets e. Professional communication.

1. MetaboliteI. Plasma

a. Plasma concentration vs. time profile analysisb. Computer aided instruction and simulation c. Problem sets d. Professional communication.


G: Biopharmaceutical factors

1. AbsorptionI. PhysiologyII. Mechanisms


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III. Physiological changes with age, sex, disease 2. Distribution

I. DiffusionII. Cardiac output / blood perfusionIII. Physical properties of the drugIV. Physical properties of the bodyV. Physiological changes with age, sex, disease

3. MetabolismI. Biotransformation methodsII. First pass effectIII. ClearanceIV. Physiological changes with age, sex, disease

4. ExcretionI. RenalII. BiliaryIII. Mammary IV. SalivaryV. Misc.VI. Physiological changes with age, sex, disease

H: Oral dosing1. Parent compound

I. Plasmaa. Plasma concentration vs. time profile analysisb. Computer aided instruction and simulation c. Problem sets d. Professional communication.


2. MetaboliteI. Plasma

a. Plasma concentration vs. time profile analysisb. Computer aided instruction and simulation c. Problem sets d. Professional communication.

II. Urine a. Amount vs. time profile analysis b. Rate vs. time profile analysis c. Computer aided instruction and simulation


Introduction

d. Problem sets e. Professional communication.

I: Bioavailability, Bioequivalence, Drug product selection1. Relative and Absolute Bioavailability2. Factors Influencing Bioavailability3. Methods of Assessing Bioavailability

I. in vivoII. in vitroIII. Correlation

4. Bioequivalence5. Bioavailability6. Drug Product Selection

1.8.2 STUDY GROUP 2: UTILIZE THE TOOLS TO OPTIMIZE PATIENT THERAPY UNDER MULTIPLE DOSE CONDITIONS,

J: Dosage regimen (Healthy, aged and diseased patients) 1. Multiple dose kinetics2. Optimization of dosage regimen3. Computer aided instruction4. Computer simulation and problem sets5. Computer aided consultation6. Professional consultation process

1.8.3 STUDY GROUP 3: APPLY THE TOOLS TO PREDICT THE CHANGES IN RELEVANT PHARMACOKINETIC PARAMETERS IN THE COMPROMISED PATIENT PATIENT WITH SELECTED DISEASES,

L. Clearance objectives:1. Given patient information regarding organ function, the student will calculate (III)

changes in clearance and other pharmacokinetic parameters inherent in compromised patients.

1.8.4 STUDY GROUP 4: APPLY THE TOOLS IN SPECIAL CASES.

K: Multicompartment Modeling 1. Parent compound plasma vs. time profile analysis2. Multiple dose considerations3. Computer aided instruction 4. Computer simulation and problem sets


Introduction

5. Computer aided consultation 6. Professional consultation process

L: Protein Binding (healthy, aged and diseased patients)1. Mass balance considerations / drug interactions2. Effects of protein binding on pharmacokinetic parameters3. Computer aided instruction 4. Computer simulation and problem sets 5. Computer aided consultation 6. Professional consultation process

M: Non - linear (Michaelis - Menton) kinetics1. Computer aided instruction 2. Computer simulation and problem sets 3. Computer aided consultation 4. Professional consultation process

End of material for Masters / Honors course


Introduction

1.9 Competency Statements Related To Pharmacokinetics

The profession of pharmacy has determined that there are minimum, entry levelabilities necessary for a pharmacist. These form the Standards of Practice for theprofession of pharmacy, as written by The National Association of Boards of Phar-macy (who make the NABPLEX, coincidentally). It is important to note that theseabilities are not thought up by some faculty member who sits in his ivory towersaying what he thinks is important. These are what pharmacists do. They havebeen promulgated as competency statements They are also the basis for the stateboard exams as well as the basis far your coursework while in the School of Phar-macy. They are broken down into five general areas:

1.00.00 Interpreting and dispensing prescriptions/ medication orders,

2.00.00 Assessing prescriptions/ medication orders and the drugs used in dispensing them,

3.00.00 Compounding and calculations involved in extemporaneous preparation of prescriptions/ medicationorders,

4.00.00 Monitoring drug therapy,

5.00.00 Counseling patients and health professionals.

For a complete listing of competency statements please refer to the NABPLEXCandidate’s Review Guide, published by the National Association of Boards ofPharmacy.

1.9.1 SPECIFIC COMPETENCY STATEMENTS ADDRESSED IN THIS COURSE

1.00.00 Interpreting and Dispensing Prescriptions/ Medication Orders

1.04.00Given a prescription or medication order, the candidate shall identify or explain the rationale for thedosage regimen.

1.04.03The candidate shall calculate the dose or rate of administration of a drug when given appropriate data.

2.00.00 Assessing Prescriptions/Medication Orders and the Drugs Used in Dispensing Them

2.01.00 The candidate shall identify, interpret, or explain patient or pharmacokinetic factors that affect either theefficacy or safety of individual drug therapy.

2.01.01The candidate shall relate the influence of patient factors (e.g., age, weight, sex, occupation, compli-ance, exercise, stress, placebo effect, vital organ function) to the choice or dosage of drug therapy.

2.01.02 The candidate shall explain or apply biopharmaceutical principles or pharmacokinetic factors (e.g.,absorption, distribution, metabolism, excretion) as they relate to dosage regimen design or evaluation of experi-mental or patient data, including the: definition or explanation of biopharmaceutical terminology; recognition ofthe effects of patient health status or concurrent drug therapy on bioavailability; determination of pharmacokineticparameters or dosing regimens (e.g., loading dose estimations, maintenance dose calculation, elimination half-


Introduction

life, determinations of clearance, or volume of distribution); or recognition of biosocial factors that affect pharma-cokinetic parameters (e.g., smoking, alcohol consumption, work environment.

2.03.00 Given appropriate information or data regarding bioavailability, the candidate shall demonstrate properjudgment to assure safe and effective drug therapy.

2.03.01The candidate shall interpret or utilize in vitro dissolution test results that are used to predict bioequiv-alence or shall distinguish these from in vivo tests.

2.03.02 The candidate shall differentiate between relative and absolute bioavailability.

2.03.03 The candidate shall interpret area under plasma concentration versus time curves as an assessmentof bioavailability.

2.03.04 The candidate shall explain or interpret the effect of rate of absorbtion on maximum plasma concentra-tions and times of maximum plasma concentrations after drug administration.

2.04.00 The candidate shall identify, interpret, or evaluate sources of information for clarifying or answeringquestions related to prescriptions, medication orders, or health care.

2.04.01 The candidate shall select appropriate books or references containing needed information (e.g.,bioequivalence, incompatibility, drugs for emergency situations, physicochemical stability).

2.04.02 The candidate shall evaluate the suitability, accuracy, or reliability of information (e.g., pharmacokineticcharacteristics untoward effects, therapeutic efficacy) from literature sources.

4.00.00 Monitoring Drug Therapy

4.01.02 The candidate shall identify, collect, or evaluate patient information that relates to the effectiveness ofdrug therapy (e.g., clinical observations, pharmacokinetic data, laboratory test results, sensitivities).

5.00.00 Counseling Patients and Health Professionals

5.01.00 The candidate shall counsel a patient or health professional regarding the indications, benefits, admin-istration, storage, or untoward effects of prescription medications.

5.01.01 The candidate shall explain the proper procedure for taking or administering the drug (e.g., dosage,time of day, method or time of administration -- before or after meals, duration of use), or for providing auxiliaryinstructions about the medication.

5.01.03 The candidate shall explain cautions regarding food, drugs, chemicals, or nutrients that should beavoided while particular medications are taken.

5.05.00 The candidate shall advise consumers regarding the selection, proper use, effects, precautions, orcontraindications of OTC products.

5.05.03 The candidate shall explain how a drug is to be taken (e.g., dosage, time of day, frequency, before orafter meals).


Introduction

1.10 Pharmacokinetic Symbolism

Pharmacokinetics was developed in several locations simultaneously. Because ofthis, the symbols used in the literature are not consistent. Provided each symbol isrigorously defined prior to use, this inconsistency should not prove an insurmount-able difficulty when assessing the literature. In this book, the symbolism belowwill be generally used, though, as an illustration of the variety, some deviation maybe anticipated on occasions.

1.10.1 AMOUNT TERMS (UNIT: MASS)

amount remaining to be eliminated (excreted)

dose (or maintenance dose)

loading dose

amount of drug remaining to be absorbed at any time

amount of unchanged drug in body at any time

amount of metabolite in body at any time

cumulative amount of unchanged drug excreted into urine up to any time

cumulative amount of metabolite excreted into urine up to any time

maximum amount of unchanged drug in body

minimum amount of unchanged drug in body

average amount of unchanged drug in body (also Laplace transform)

minimum amount of unchanged drug in body necessary for pharmacologi-

cal response

ARE

D

DL

Xa

X

Xm

Xu

Xmu

Xmax

Xmin

X

Xeff


Introduction

sing

1.10.2 CONCENTRATION TERMS (UNITS MASS/VOLUME)

concentration of drug in blood at any time

concentration of drug in plasma at any time

Concentration of metabolite in plasma (or blood) at any time

“average” steady-state concentration of drug in plasma during a do

interval

maximum concentration of drug in plasma

minimum concentration of drug in plasma

average concentration of drug in plasma

dissociation constant of drug-protein complex

Michaelis-Menton rate constant

dissociation constant of drug-receptor complex

minimum effective concentration of drug or metabolite

minimum toxic concentration of drug or metabolite

Cb

Cp

Cm

Cp( )ss

avg

Cp( )ss

max

Cp( )ss

min

Cp

KA

KM

KR

MEC

MTC


Introduction

1.10.3 VOLUME TERMS (UNIT: VOLUME)

apparent volume of unchanged drug distribution in compartment

apparent volume of metabolite distribution in compartment

physiological volume of plasma water

1.10.4 TIME TERMS (UNIT: TIME)

time since administration of dose

duration of zero-order input

time since cessation of zero-order input

lag time

mean time during sampling interval

elimination half-life (“biological half-life”)

time for 50% removal

time when maximum amount or concentration occurs

duration of effective pharmacological response

dosing interval (greek theta)

time variable used in association with zero-order input

Vd

Vm

Vw

t

T

t'

t0

t

t½

t0.5

tmax

tdur

τ

b


Introduction

1.10.5 RATE CONSTANT TERMS (UNIT: RECIPROCAL TIME (*), MASS/TIME (**))

, apparent first-order rate constant for elimination, Summation of all the

ways the drug is eliminated (*)

apparent first-order rate constant for absorption (*)

apparent first-order rate constant for urinary (renal) excretion of unchanged

drug (*)

apparent first-order rate constant for metabolism of unchanged drug (*)

apparent first-order rate constant for excretion of metabolite (*)

apparent first-order transfer rate constant (*)

zero-order input rate constant (**)

zero-order infusion rate constant (**)

rate constant for decline in pharmacological effect (usual units:%/time)

hybrid first-order rate constant (*) (greek alpha)

hybrid first-order rate constant (*) (greek beta)

K ke Ki,,

ka

ku k,r

km

kmu

kij

k0

Q

R

α

β


Introduction

1.10.6 CLEARANCE TERMS (UNITS: VOLUME/TIME)

total body clearance (TBC)

renal clearance (RC)

metabolic clearance (MC)

creatinine clearance

hepatic clearance (HC)

1.10.7 RATE TERMS (UNITS: MASS/TIME (*), MASS/TIME, VOLUME (**), VOLUME/TIME (***)

instantaneous rate of change of amount of unchanged drug (*)

measured rate of change of amount of unchanged drug (*)

rate of plasma flow through the liver (***)

rate of plasma flow through the kidney (***)

theoretical maximum rate of a process (**)

1.10.8 OTHER TERMS

area under the plasma concentration-time curve (units: time * mass/vol-ume)

area under the first moment of the plasma concentration-time curve (units:

)

Mean Residence Time (units: )

Cl

Clr

Clm

Clcr

ClH

dXdt-------

Xt----

RH

Rr

VM

AUC

AUMC

time2

mass⋅ volume⁄

MRT time


Introduction

Mean Absorption Time (units: )

Mean Dissolution Time (units: )

intensity of pharmacological effect

steady-state hepatic extraction ratio

steady-state renal extraction ratio

maximum intensity of pharmacological effect

fraction of administered dose ultimately absorbed

fraction remaining to be eliminated (excreted)

hematocrit (fractional volume of erythrocytes in whole blood)

number of elimination half-lives in a dosing interval

accumulation factor

intercept

fraction of drug that is free (unbound)

fraction of steady-state

slope (sometimes specifically for log dose-response plot)

number of doses

Laplace operator

indicates molar concentration

MAT time

MDT time

E

EH

Er

Emax

F

FRE

H

N

R

b

f

fss

m

n

s

[ ]


Introduction

1.10.9 SUBSCRIPTS

at time zero

at time infinity

during steady-state

at time t

at time T

following dose n

difference between extrapolated and observed

intrinsic

index (i.e., 1,2,3)

index (i.e., 1,2,3)

1.10.10 SUPERSCRIPTS

extrapolated

last measured value

0

∞

ss

t

T

n

diff

int

i

j

x

x°


Introduction

1.11 First Lesson in Pharmacokinetics

It should be intuitively obvious to the most casual observer that the relative bio-availability of 2 simultaneous I.V. bolus doses of a drug is equal to the following:

(EQ 4-1)

given that 100% bioavailability of a single I.V. bolus dose is equal to 1, and bothdoses contain an equal mass of active drug.

For the struggling pharmacokinetics student, we would like to show the veracity ofthis statement. Of course, it is obvious that; the reverse of the transpose is equal tothe transpose of the inverse in matrix theory. i.e.:

(EQ 4-2)

Also, it should be obvious that:

(EQ 4-3)

Consequently,

(EQ 4-4)

which means that:

(EQ 4-5)

By definition,

(EQ 4-6)

and

(EQ 4-7)

Thus:

x1[ ]

1–x

1–[ ]1

–( )! 1δ---+

δ

δ ∞→lim

ln qsin( )2qcos( )2

+ + p 1 ptanh( )2–cosh

2n

--------------------------------------------------

n 0=

∞

∑=

x1[ ]

1–x

1–[ ]1

=

0! 1=

x1[ ]

1–x

1–[ ]1

–( )! 1=

11δ---+

δ

δ ∞→lim

ln qsin( )2qcos( )2

++ p 1 ptanh( )2–cosh

2n

--------------------------------------------------

n 0=

∞

∑=

e 11δ---+

δ=

1 p 1 ptanh( )2–cosh=


Introduction

(EQ 4-8)

Also,

(EQ 4-9)

and

(EQ 4-10)

and

(EQ 4-11)

So, as we observed in equation 1,

(EQ 4-12)

under the stated conditions, two I.V. bolus doses given simultaneously will havetwice as much available drug as a single I.V. bolus dose.

You will agree, however, equation 1-1 is obvious and therefore is more easilyunderstood by a pharmacokineticist!

eln qsin( )2qcos( )2

+ + 1

2n

-----

n 0=

∞

∑=

2 1

2n

-----

n 0=

∞

∑=

1 eln=

1 qsin( )2qcos( )2

+=

1 1+ 2=


introduction - basic pharmakokinectics

Health & Medicine

course objectives

compromised patient

successful student

patient therapy

course study group

credit course

single dose patient

study of pharmacokinetics