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Introduction - Basic Pharmakokinectics

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Introduction - Basic Pharmakokinectics

Introduction - Basic Pharmakokinectics

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  • 1. Introduction CHAPTER 1 Author: Michael Makoid and John Cobby Reviewer: 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 1-1 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf/
  • 2. Introduction 1.1 Basic Pharmacokinetics Pharmacokinetics is the mathematics of the time course of Absorption, Distribu- What is pharmacokinet- ics? 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. 1-2 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 3. 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 • Calculate (III) patient and drug specific pharmacokinetic parameters from patient data, do? • 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 • Study Group 1: Learn the tools used by the discipline. Calculate patient and drug specific phar- arranged? 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, each with their own set of general objectives as shown below: 1-3 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 4. Introduction 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 1. Given a data set containing a pair of variables, the student will properly construct (III) var- to be able to do? How ious graphs of the data. will examination ques- 2. Given various graphical representations of data, the student will calculate (III) the slope tions be written for this and intercept by hand as well as using linear regression. material? 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 ( V d , K, k m , k r , AUC , 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 analysis 3. Given patient specific pharmacokinetic parameters, the student shall provide professional communication regarding IV bolus/infusion information 4. The student shall utilize computer aided instruction and simulation 5. 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 ( V d , K, k m , k r , AUC , Clearance, MRT) from IV data. 1-4 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 5. Introduction D. Biopharmaceutical factor objectives: the student shall be able to discuss: 1. physiology and mechanisms of absorption 2. effects of diffusion, cardiac output / blood perfusion, physical properties of the drug and body on distribution 3. biotransformation, first pass effect, and clearance 4. 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 ( V d , K, k m , k r , k a , AUC , 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, T p and ( C p )max ). 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. 1-5 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 6. Introduction 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( V d1 , Alpha, A 1 , Beta, B 1 , k 10 , k 12 , k 21 , AUC , 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. 1-6 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 7. Introduction 1.3 Exams Exams will consist of problems which will be linked directly back to an objective How are the exams made? (above) and a library assignment in which you will be asked to evaluate a research article with the tools available to you by the time of the exam as discussed below. 1-7 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 8. Introduction 1.3.1 LIBRARY ASSIGNMENT IN PHARMACOKINETICS K. Library Assignment Objectives What do I have to do in 1. Given a suitable primary research article in the area of pharmacokinetics, the student shall the library? 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”: 1. Tell me what type of paper you have chosen to evaluate: How should the paper look? The problem sets show what data you need for each of these. First Exam What content should I IV Bolus Parent compound 50 pts look for in the paper and IV Bolus Parent metabolite 65 pts what is its relative IV Infusion 65 pts worth? 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 evalu- ate the data. 4. Do analysis of data by hand and by PK Solutions. 5. Compare your work with the author’s (short paragraph). 1-8 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 9. Introduction 6. Comment on any differences of parameter calculation or interpretation. See objectives above (Paragraph). 7. Write an exam question to obtain pharmacokinetic parameters. You know from the first exam what they should look like. Each of the above sections is designed to bring the student an understanding of the Why do I need to do this library assignment? information and the processes necessary to operate as a competent professional in the area of pharmacokinetic evaluation and consulting. Consequently, the course will evolve from a quantitative, manipulative mathematics course to a course which stresses communication skills. Consults will be graded not only on content (the proper dosage regimen for the patient) but also grammar, punctuation, spelling, organization and neatness. You may have the best medical information in the world, but if it is poorly executed, it will be ignored. This course will probably be one of the more rigorous ones that you will have Can I cram the night before? experienced in your college career to date. It will be one of the first ones which attempt 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 a big IF) taken slowly, in small bites. Its just like eating an elephant - you can’t do it all 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!). In many 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 that the requirements and expectations of a professional school are considerably more than your undergraduate experience and it most likely will not work in many courses which require assimilation of the information presented, as is expected in a professional program. 1-9 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 10. Introduction 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: I. To Know: means to memorize (recognize, recall) (Many college courses What is cramming good for? Lowest level of cog- require only this level of cognitive effort, hence the extensive experience with nitive skills. “multiple guess” exams). II. To Comprehend: means to translate; to be able to put information into your own words. (Essay exams routinely call for this level of effort on the part of the student). III. To Apply: means to be able to use knowledge, rules and principles in an This is where we begin. unfamiliar situation. (This is the lowest level of skill necessary to function at a technician level). IV. To Analyze: means to be able to critically examine a body of knowledge This is where we need to be in school. and to be able to identify the relationships. (This is where a B.S. graduate should operate. Education obviates the need for teachers.) V. To Synthesize: means to put together information, not necessarily previ- This is where we need to be as graduates. ously so organized, in order to get a new piece of information. (This is the begin- ning level of professional judgment). VI. To Evaluate: means to be able to judge the worth of an idea, form hypothe- ses and do problem solving, research, invent new knowledge. (This is the doctoral level of participation in the area). A professional routinely operates at level IV and V with occasional forays into Can’t I just do it the same way that I have level VI. This is where you will operate in this course and in most subsequent always studied? courses in the professional curriculum. You will note that each of the objectives for the course contains specific action words followed by the level in the taxonomy at which 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 or recognize the right answer. Problems challenge thinking skills and demand the synthesis of material into concepts. To facilitate this transition we both must work very hard. 1-10 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 11. Introduction 1.5 Course Contract I Will: 1. Provide individualized learning methods: Some students learn by hearing What will the teacher do in this class? Act as a and others by seeing (auditory or visual learners). I have designed the course to facilitator. accommodate both types of learners. In class, I will provide you with executive summaries of what you read. I will provide group leaders with detailed reviews of materials for which they are responsible. I will tell you what I’m going to say, say it, 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 and with the homework problems. I will provide you with ample examples of the types of manipulations that you will be expected to do. I will provide you with ample problem sets so that you may practice those manipulations. I will provide you with computer simulations so that you may see these manipulations in action and begin to get a feel for the numbers and their magnitude. Feedback and interaction is encouraged. If I am not meeting your perceived needs, you must tell me. Some students might feel too intimidated to ask questions. To obviate this problem, you will elect a group team leader, an ombudsman, whose job it will be to carry your questions, concerns, and comments to me. It is your job and his responsibility to see that the group interaction facilitates the learning process. This is not to prevent you coming to see me but offered as another avenue of communication. 2. Provide clinical relevance to the practice of pharmacy. This will be stressed Will I learn anything rel- evant in this course? at all times. I will also relate real clinical experiences; virtually all of the problems come from real patients. Some educators believe examples must fit the theory exactly. This gives the student a false set of reality parameters. Consequently, when “the data does not fall on the line” the student rejects relevant information. You will become familiar with real data, and the problems associated with real data. 3. Give adequate feedback: Evaluation of your performance will be available How will I know how I’m doing? to you at all times. A running evaluation, updated weekly will be on my door for your review. You may check any thing with me at any time. I expect that you will see me outside of class time either individually if you need help or in supervised review sessions. You must see me for assistance if your performance is unsatis- factory. 4. Teach: As an operational definition this means: clarifying what you read, What will the teacher be doing? Engaging you in demonstrating how and why things work as they do, and unifying the material - an active learning pro- attempting to generate the A - HA! syndrome. The correlate of teach from the stu- cess. dent view is learn. Neither is a passive process. I can not open your head and pour the knowledge in. A saying in education is: “Knowledge maketh a bloody entrance”. You must expend the effort necessary for you to learn. 1-11 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 12. Introduction 5. Facilitate Learning. You received objectives (above) and a summary for What must I do in this active learning process? each study section (chapters in this text), of exactly what is expected of you with You MUST participate in examples in the problem sets at the end of each chapter. We will have ample time class and in your during class to field questions generated by the correlated reading and problem assigned groups!!! sets, 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 me and your fellow colleagues. Remember - the class is to help you learn. It is not the sole means of learning, nor am I the source of all knowledge. Its’ only reason for being is to help you organize and summarize what you learn. It has a relatively simple plan with multiple examples. From these examples you will develop con- cepts which will obviate the need for memorizing individual facts (or actually me entirely). I will assist you in the formation of these concepts. It is patently obvious that I can not give you every possible example of every type of question that you will be asked during your professional career. For one thing I don't know what questions you will be asked nor problems you will encounter. Going from the spe- cific to the general forms concepts which will allow you to go from the general to the specific, even if you have never been there before. The total medical knowl- edge is now doubling at a rate of every 4 years. I can not teach you the content nec- essary 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 at least in Bloom's level V. 6. Be available: I do not have office hours. I believe them to be restrictive How do I get in touch with the teacher? from your view point. What I do have is a schedule calandar preparede weeks in advance of when I am NOT available. You may set an appointment, at least a 1/2 day in advance to guarantee that I see it, any other time. Of course, appointments are not necessary if I'm in my office, but you take the chance of my not being there or someone else being there ahead of you if you do not sign up. You may contact me by e-mail: makoid@creighton.edu, or by phone: 402-280-2952. You may also- contact my secretary, Dawn Trojanowski in the departmental office or by phone 402-280-2893 to make an appointment. 7. Be responsive: Each day, you will be asked to provide me with a one How can I tell the teacher how things are minute summary of the topic consisting answering the following questions: going? a. What was the main thrust of the study section (What did you read)? 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 as a framework of what to stress and what to change. 1-12 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 13. Introduction After each exam, in addition to working out the problems, we will decide whether Do I have any say in the examination questions? any individual question was not covered by the objectives. Note: Not that it was tough, not that you got it wrong, not that it didn’t allow you to tell me what you knew, but did I tell you that I was going to ask you to do it? (Was it covered by the objectives?) 8) Evaluate your performance fairly and honestly: Quite simply, I’m going to tell How are the exams graded? you what I expect that you will do. I will show you how to do it. I will provide you with practice in doing it. I will provide you with an exam which tests your ability to 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 state board exams (and hopefully real life). Like both of these situations, all answers are interconnected. What that means is, if you improperly calculate a parameter which is needed to make another calculation which is used to make a third, etc. ALL are wrong. 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 elimination rate constant and ended up killing your patient. You Will: 1) Come prepared to participate in class. This is your full time job. If you are What do I have to do? How much work is really working full time, it is usually 40 to 60 hours per week. If you go to college 15 to expected? 18 credits and prepare/study 2 hours for each credit, you work 45 to 55 hour per week - you have a full time job. Your commitment is the 45 to 50 hour week not just the contact hours and a night for each exam. This specifically means for each 1 hour class, I expect no less than 2 hours of preparation on your part. Each of you will be assigned to a study group. You will work the problems together and teach each other both in and out of class. We will have group discussion of class as well as group problem solving. It will be your responsibility that every member of your group be adequately prepared to answer for the group during recitation. There will be a grade for group participation. Part of your grade will be based on your peer evaluation. 2) Read the text. When you read, read critically. Do you understand each idea? Do I have to read the text? Each page in the HTML version has an evaluation section. If you get it you will be asked to be a resource for that page for your peers. If you don’t get it, you will be directed to your peers to seek help. Come prepared to ask about it in class. 3) Work the problems. Check the answers. These come from old exams, so they Why do I have to do the problem sets? are the type that you are likely to see. Work them in your study groups so that everyone can see your thought processes. Bring them to class if you can not do them 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 your thought. I will not work the problem for you. You would not learn if I did it for you. It is crucial that you work the problems. Each has a specific objective. Over- 1-13 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 14. Introduction all, they contribute to your gaining facility in the processes that a pharmacokineti- cist must know how to do. 4) Do not delude yourself with respect to your performance. If you received a Can I just coast through? grade that was less than satisfactory for you, do not simply console yourself by saying “I knew the stuff, I just made a little error.” Can you get it right consis- tently? That's when you know the stuff. That is not a laudable goal. That's what a professional does. There have been several students in the past that “knew that stuff” right up till the time that they had to repeat the course (and sometimes beyond). 1-14 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 15. Introduction 1.6 Computers in the course Computer literacy is necessary in this field. Consequently computers will pervade Can I get through with just paper and pencil? the course. The homework problems (above) are to done both by hand and checked with the computer. This will help your understanding of pharmacokinetics in general and that homework objective in particular. Computers are natural adjunctive tools in the teaching of pharmacokinetics. The are able to simulate the concentration vs. time profiles and do difficult repetitive calculations which allow the student to get a broad view of the processes involved. Program that is becomming the industry standard and is currently being used in the What are the programs that I will be using? course is PK Solutions. We have a site licence for it and a working copy is in the computer lab. It is a required text for the course. You will need to learn to use the software as complete instructions are available with its purchase. In addition to the above course objectives, there are specific objectives for the use of computers in the course. They are: What will I be expected • Simulation. The student will be able to utilize appropriate graphs and histograms used classical to do with the comput- pharmacokinetics in the course. The student will demonstrate effects of changes in pharmacoki- ers? 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 method is the solution of the problem sets by computer. First, I expect that you would do the problem by hand, complete with graphs and other supporting calculations fol- lowed by computer simulation and data analysis. Just how close did you come to the best fit? Next, a portion of each exam will be a library exercise in which you will find and evaluate a published article according to the principles that you learned in class utilizing the computer facilities. How close did you come the authors numbers? Do you, in fact, even agree with the authors? You will prepare a short consult in which you describe the patient and what the authors did along with your support (or non-support) of the authors conclusions. 1-15 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 16. Introduction 1.7 Survival Kit 1.7.1 THINGS FOR YOUR SURVIVAL KIT! x 1. You will need a good calculator - One with and functions. You must What do I need to buy e ln x RIGHT NOW? have it ASAP. You will use it in class. 2. You will also need 2 cycle semilog paper and a clear straight edge ruler for use in class. These are available in the book store or at an office supply store. You can also downoad a copy of graph paper printer for you own personal use. A copy is 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 all the pages in this book as well as your class notes. Work in your study groups. You never learn it so well as when you teach it to What do I need to do in and out of class? someone else. Everyone benefits from a well run prepared study group. You are not in competition with your fellow classmates. If everyone earns an “A”, then everyone will receive one. Organize and label your study notes. This is basic survival. This is one strategy How can I organize this material? that I find works well. I recommend it highly. Good study notes are formatted on loose-leaf in a three ring binder. The individual pages have a line drawn down about 1/3 the way in. The notes are taken on the right (2/3) of the page, while labels go in the left. The labels on the left are often written as questions, which are answered in the text on the right. Loose leaf binders allow for the incorporation of reading summaries as well as relevant problems and homework to be organized with a divider all in one place. You should write intelligently, with proper punctua- tion and spelling as if you were preparing a consult for a physician. Organization is the key. Remember: you may have all the information in the world at your fingertips; be able to solve the most difficult therapy problem and no one will listen to you if you can't communicate intelligently. You will be required to communicate in this course utilizing both written and verbal skills. Chapters in the book will be organized as above. 1-16 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 17. Introduction 1.7.2 WHAT YOU WILL GAIN: (YOUR GOALS) 1. At the lowest level, a decent grade for a significant course. Specific grades How is the course to be graded? will 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: 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 You will be require to pass the first exam before you are allowed to take the second. 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 with regard to pharmacokinetics. 3. You will gain a useful skill that will make you an integral part of the health care team. 4 You will learn to learn. There is an old proverb which goes: “Give a man a Do I really need a teacher to learn? fish and you feed him for a day. Teach a man to fish and you feed him for a life- time.” The B.S. Degree is designed to eliminate teachers. An educated man is one who has learned to how to learn, not one who memorized a page in a book. That is what you need to be a professional. The total medical knowledge is doubling at a rate of every 3-4 years. That means that you will be out of date shortly after gradu- ation (if not before) if you simply memorized content and don't learn to learn and continue to learn throughout your career. 1-17 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 18. Introduction One last piece of information: Neither you nor I will not tolerate any academic What about cheating? misconduct. Anyone caught will minimally receive an “F” for their efforts and I will recommend dismissal from the program. The profession has no room for unprofessional behavior. I will prosecute. 1-18 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 19. Introduction 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: Introduction 1. Texts 2. Literature 3. Grading Policy 4. Course Philosophy B: Math review 1. Numbers and exponents 2. Graphs and reaction order 3. Calculus 4. Laplace transform 5. Computer Introduction 6. Computer simulation and problem sets C: Pharmacokinetic modeling 1. What a model is and what it isn’t. 2. Why we model 3. Philosophy of modeling D: Pharmacological Response 1. Michaelis - Menton Mass balance equation 2. Interrelationships between Concentration, time and response. E: I.V. Bolus dosing 1. Parent compound I. Plasma a. Plasma concentration vs. time profile analysis b. 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 d. Problem sets 1-19 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 20. Introduction e. Professional communication. 2. Metabolite I. Plasma a. Plasma concentration vs. time profile analysis b. 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. infusion 1. Parent compound I. Plasma a. Plasma concentration vs. time profile analysis b. 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 d. Problem sets e. Professional communication. 1. Metabolite I. Plasma a. Plasma concentration vs. time profile analysis b. 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 d. Problem sets e. Professional communication. G: Biopharmaceutical factors 1. Absorption I. Physiology II. Mechanisms 1-20 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 21. Introduction III. Physiological changes with age, sex, disease 2. Distribution I. Diffusion II. Cardiac output / blood perfusion III. Physical properties of the drug IV. Physical properties of the body V. Physiological changes with age, sex, disease 3. Metabolism I. Biotransformation methods II. First pass effect III. Clearance IV. Physiological changes with age, sex, disease 4. Excretion I. Renal II. Biliary III. Mammary IV. Salivary V. Misc. VI. Physiological changes with age, sex, disease H: Oral dosing 1. Parent compound I. Plasma a. Plasma concentration vs. time profile analysis b. 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 d. Problem sets e. Professional communication. 2. Metabolite I. Plasma a. Plasma concentration vs. time profile analysis b. 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 1-21 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 22. Introduction d. Problem sets e. Professional communication. I: Bioavailability, Bioequivalence, Drug product selection 1. Relative and Absolute Bioavailability 2. Factors Influencing Bioavailability 3. Methods of Assessing Bioavailability I. in vivo II. in vitro III. Correlation 4. Bioequivalence 5. Bioavailability 6. 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 kinetics 2. Optimization of dosage regimen 3. Computer aided instruction 4. Computer simulation and problem sets 5. Computer aided consultation 6. 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 analysis 2. Multiple dose considerations 3. Computer aided instruction 4. Computer simulation and problem sets 1-22 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 23. Introduction 5. Computer aided consultation 6. Professional consultation process L: Protein Binding (healthy, aged and diseased patients) 1. Mass balance considerations / drug interactions 2. Effects of protein binding on pharmacokinetic parameters 3. Computer aided instruction 4. Computer simulation and problem sets 5. Computer aided consultation 6. Professional consultation process M: Non - linear (Michaelis - Menton) kinetics 1. Computer aided instruction 2. Computer simulation and problem sets 3. Computer aided consultation 4. Professional consultation process End of material for Masters / Honors course 1-23 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 24. Introduction 1.9 Competency Statements Related To Pharmacokinetics The profession of pharmacy has determined that there are minimum, entry level abilities necessary for a pharmacist. These form the Standards of Practice for the profession of pharmacy, as written by The National Association of Boards of Phar- macy (who make the NABPLEX, coincidentally). It is important to note that these abilities are not thought up by some faculty member who sits in his ivory tower saying what he thinks is important. These are what pharmacists do. They have been promulgated as competency statements They are also the basis for the state board 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/ medication orders, 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 NABPLEX Candidate’s Review Guide, published by the National Association of Boards of Pharmacy. 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 the dosage 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 the efficacy 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 of the effects of patient health status or concurrent drug therapy on bioavailability; determination of pharmacokinetic parameters or dosing regimens (e.g., loading dose estimations, maintenance dose calculation, elimination half- 1-24 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 25. 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 proper judgment 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 assessment of 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 answering questions 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., pharmacokinetic characteristics 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 of drug 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 auxiliary instructions about the medication. 5.01.03 The candidate shall explain cautions regarding food, drugs, chemicals, or nutrients that should be avoided while particular medications are taken. 5.05.00 The candidate shall advise consumers regarding the selection, proper use, effects, precautions, or contraindications 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 or after meals). 1-25 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 26. Introduction 1.10 Pharmacokinetic Symbolism Pharmacokinetics was developed in several locations simultaneously. Because of this, the symbols used in the literature are not consistent. Provided each symbol is rigorously defined prior to use, this inconsistency should not prove an insurmount- able difficulty when assessing the literature. In this book, the symbolism below will be generally used, though, as an illustration of the variety, some deviation may be anticipated on occasions. 1.10.1 AMOUNT TERMS (UNIT: MASS) ARE amount remaining to be eliminated (excreted) D dose (or maintenance dose) DL loading dose Xa amount of drug remaining to be absorbed at any time X amount of unchanged drug in body at any time Xm amount of metabolite in body at any time Xu cumulative amount of unchanged drug excreted into urine up to any time X mu cumulative amount of metabolite excreted into urine up to any time X max maximum amount of unchanged drug in body X min minimum amount of unchanged drug in body X average amount of unchanged drug in body (also Laplace transform) X eff minimum amount of unchanged drug in body necessary for pharmacologi- cal response 1-26 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 27. Introduction 1.10.2 CONCENTRATION TERMS (UNITS MASS/VOLUME) Cb concentration of drug in blood at any time Cp concentration of drug in plasma at any time Cm Concentration of metabolite in plasma (or blood) at any time ss (Cp ) “average” steady-state concentration of drug in plasma during a dosing avg interval ss (Cp ) maximum concentration of drug in plasma max ss (Cp ) minimum concentration of drug in plasma min Cp average concentration of drug in plasma KA dissociation constant of drug-protein complex KM Michaelis-Menton rate constant KR dissociation constant of drug-receptor complex MEC minimum effective concentration of drug or metabolite MTC minimum toxic concentration of drug or metabolite 1-27 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 28. Introduction 1.10.3 VOLUME TERMS (UNIT: VOLUME) Vd apparent volume of unchanged drug distribution in compartment Vm apparent volume of metabolite distribution in compartment Vw physiological volume of plasma water 1.10.4 TIME TERMS (UNIT: TIME) t time since administration of dose T duration of zero-order input t' time since cessation of zero-order input t0 lag time t mean time during sampling interval t½ elimination half-life (“biological half-life”) t 0.5 time for 50% removal t max time when maximum amount or concentration occurs t dur duration of effective pharmacological response τ dosing interval (greek theta) b time variable used in association with zero-order input 1-28 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 29. Introduction 1.10.5 RATE CONSTANT TERMS (UNIT: RECIPROCAL TIME (*), MASS/TIME (**)) K, ke ,K i , apparent first-order rate constant for elimination, Summation of all the ways the drug is eliminated (*) ka apparent first-order rate constant for absorption (*) k u, k r apparent first-order rate constant for urinary (renal) excretion of unchanged drug (*) km apparent first-order rate constant for metabolism of unchanged drug (*) k mu apparent first-order rate constant for excretion of metabolite (*) k ij apparent first-order transfer rate constant (*) k0 zero-order input rate constant (**) Q zero-order infusion rate constant (**) R rate constant for decline in pharmacological effect (usual units:%/time) α hybrid first-order rate constant (*) (greek alpha) β hybrid first-order rate constant (*) (greek beta) 1-29 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 30. Introduction 1.10.6 CLEARANCE TERMS (UNITS: VOLUME/TIME) Cl total body clearance (TBC) Cl r renal clearance (RC) Cl m metabolic clearance (MC) Cl cr creatinine clearance Cl H hepatic clearance (HC) 1.10.7 RATE TERMS (UNITS: MASS/TIME (*), MASS/TIME, VOLUME (**), VOLUME/TIME (***) dX ------ - instantaneous rate of change of amount of unchanged drug (*) dt X --- - measured rate of change of amount of unchanged drug (*) t RH rate of plasma flow through the liver (***) Rr rate of plasma flow through the kidney (***) VM theoretical maximum rate of a process (**) 1.10.8 OTHER TERMS AUC area under the plasma concentration-time curve (units: time * mass/vol- ume) AUMC area under the first moment of the plasma concentration-time curve (units: 2 time ⋅ mass ⁄ volume ) MRT Mean Residence Time (units: time ) 1-30 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 31. Introduction MAT Mean Absorption Time (units: time ) MDT Mean Dissolution Time (units: time ) E intensity of pharmacological effect EH steady-state hepatic extraction ratio Er steady-state renal extraction ratio E max maximum intensity of pharmacological effect F fraction of administered dose ultimately absorbed FRE fraction remaining to be eliminated (excreted) H hematocrit (fractional volume of erythrocytes in whole blood) N number of elimination half-lives in a dosing interval R accumulation factor b intercept f fraction of drug that is free (unbound) f ss fraction of steady-state m slope (sometimes specifically for log dose-response plot) n number of doses s Laplace operator [] indicates molar concentration 1-31 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 32. Introduction 1.10.9 SUBSCRIPTS 0 at time zero ∞ at time infinity ss during steady-state t at time t T at time T n following dose n diff difference between extrapolated and observed int intrinsic i index (i.e., 1,2,3) j index (i.e., 1,2,3) 1.10.10 SUPERSCRIPTS x extrapolated x° last measured value 1-32 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 33. 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: ∞ 1 δ  2 cosh p 1 – ( tanh p ) ln  lim  ( [ x ] – [ x ] )! + --  + ( sin q ) + ( cos q ) = 1 –1 –1 1 ∑ -------------------------------------------------- 2 2 - (EQ 4-1)  δ  δ → ∞ n 2 n=0 given that 100% bioavailability of a single I.V. bolus dose is equal to 1, and both doses contain an equal mass of active drug. For the struggling pharmacokinetics student, we would like to show the veracity of this statement. Of course, it is obvious that; the reverse of the transpose is equal to the transpose of the inverse in matrix theory. i.e.: 1 –1 –1 1 [x ] = [x ] (EQ 4-2) Also, it should be obvious that: 0! = 1 (EQ 4-3) Consequently, 1 –1 –1 1 ([x ] – [ x ] )! = 1 (EQ 4-4) which means that: ∞  1 δ 2 cosh p 1 – ( tanh p ) ln  lim  1 + --  + ( sin q ) + ( cos q ) = ∑ -------------------------------------------------- 2 2 -   (EQ 4-5) δ δ → ∞ n 2 n=0 By definition, 1δ e =  1 + -- -  δ (EQ 4-6) and 2 1 = cosh p 1 – ( tanh p ) (EQ 4-7) Thus: 1-33 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf
  • 34. Introduction ∞ 1 ∑ ----n 2 2 ln e + ( sin q ) + ( cos q ) = - (EQ 4-8) 2 n=0 Also, ∞ 1 ∑ ----n 2= - (EQ 4-9) 2 n=0 and 1 = ln e (EQ 4-10) and 2 2 1 = ( sin q ) + ( cos q ) (EQ 4-11) So, as we observed in equation 1, 1+1 = 2 (EQ 4-12) under the stated conditions, two I.V. bolus doses given simultaneously will have twice as much available drug as a single I.V. bolus dose. You will agree, however, equation 1-1 is obvious and therefore is more easily understood by a pharmacokineticist! 1-34 Basic Pharmacokinetics REV. 00.1.11 Copyright © 1996-2000 Michael C. Makoid All Rights Reserved http://pharmacy.creighton.edu/pha443/pdf