PHA068 SAS-1.pdf

COURSE CODE:PHA068 (BIOPHARMACEUTICS AND PHARMACOKINETICS) STUDENT ACTIVITY SHEET MODULE #1 Name: __...

COURSE CODE:PHA068 (BIOPHARMACEUTICS AND PHARMACOKINETICS) STUDENT ACTIVITY SHEET MODULE #1 Name: _________________________________________________________ Class number: _______ Section: ____________ Schedule: __________________________________ Date: ______________ Lesson title: Introduction to Biopharmaceutics and Materials: Pharmacokinetics, Overview of LADMER Pen & SAS Lesson Objectives: At the end of the lesson, you should be able to: References: 1. Describe the pharmacokinetic terms and the basic concepts Shargel, Leon. Applied in biopharmaceutics and pharmacokinetics Biopharmaceutics and 2. Understand and describe the principles of LADMER system Pharmacokinetics latest Edition, Boston: McGraw Hill, latest edition Rowland, M. Clinical pharmacokinetics and pharmacodynamics: concepts and applications (latest edition.). Philadelphia: Lippincott Williams & Wilkins Rosenbaum, S. Basic pharmacokinetics and pharmacodynamics: concepts and applications (latest edition). Philadelphia: Lippincott Williams & Wilkins. Productivity tip: Make your own flashcards by putting all the terms on one side of a card and the entire paragraph on the flip side. Test yourself using the flash cards. Repeat your process until every term seems completely familiar to you. A. LESSON PREVIEW 1) Introduction (10 mins) Drugs are substances intended for use in diagnosis, cure, mitigation, treatment, or prevention of disease. Drugs are given in a variety of dosage forms or drug products such as solids (tablets, capsules), semisolids (ointments, creams), liquids, suspensions, emulsions, etc., for systemic or local therapeutic activity. Drug products can be considered to be drug delivery systems that release and deliver drug to the site of action such that they produce the desired therapeutic effect. In addition, drug products are designed specifically to meet the patient’s needs including palatability, convenience, and safety. Drug product performance is defined as the release of the drug substance from the drug product either for local drug action or for drug absorption into the plasma for systemic therapeutic activity. Pharmaceutics is the general area of study concerned with the formulation, manufacture, stability and effectiveness of pharmaceutical dosage forms.  study of the influence of formulation on therapeutic activity of a drug product. Biopharmaceutics examines the interrelationship of the physical/ chemical properties of the drug, the dosage form (drug product) in which the drug is given, and the route of administration on the rate and extent of systemic drug absorption. Study of the factors influencing the bioavailability of the drug and the This document is the property of PHINMA EDUCATION  COURSE CODE:PHA068 (BIOPHARMACEUTICS AND PHARMACOKINETICS) STUDENT ACTIVITY SHEET MODULE #1 Name: _________________________________________________________ Class number: _______ Section: ____________ Schedule: __________________________________ Date: ______________ use of this information to optimize pharmacological and therapeutic activity of drug products Bioavailability measures the rate and extent of drug entry into the systemic circulation (bloodstream). 2) Activity 1: What I Know Chart, part 1 (5 mins) What do you Know about the topic of the day? Answer the questions given and write your answers on the first column. Leave the third column blank for now. What I Know Questions: What I Learned (Activity 4) 1. What is biopharmaceutics? 2. What is the difference between pharmacokinetics from pharmacodynamics? 3. What are the 4 pharmacokinetic processes? B. MAIN LESSON Content Notes (60 mins) The importance of the drug substance and the drug formulation on absorption, and in vivo distribution of the drug to the site of action, is described as a sequence of events that precede elicitation of a drug’s therapeutic effect This document is the property of PHINMA EDUCATION  COURSE CODE:PHA068 (BIOPHARMACEUTICS AND PHARMACOKINETICS) STUDENT ACTIVITY SHEET MODULE #1 Name: _________________________________________________________ Class number: _______ Section: ____________ Schedule: __________________________________ Date: ______________ First, the drug in its dosage form is taken by the patient by an oral, intravenous, subcutaneous, transdermal, etc. route of administration. Next, the drug is released from the dosage form in a predictable and characterizable manner. Then, some fraction of the drug is absorbed from the site of administration into either the surrounding tissue for local action or into the body (as with oral dosage forms), or both. Finally, the drug reaches the site of action. A pharmacodynamic response results when the drug concentration at the site of action reaches or exceeds the minimum effective concentration (MEC). Biopharmaceutics involves factors that influence (1) the design of the drug product, (2) stability of the drug within the drug product, (3) the manufacture of the drug product, (4) the release of the drug from the drug product, (5) the rate of dissolution/ release of the drug at the absorption site, and (6) delivery of drug to the site of action, which may involve targeting the drug to a localized area (e.g., colon for Crohn disease) for action or for systemic absorption of the drug. This document is the property of PHINMA EDUCATION  COURSE CODE:PHA068 (BIOPHARMACEUTICS AND PHARMACOKINETICS) STUDENT ACTIVITY SHEET MODULE #1 Name: _________________________________________________________ Class number: _______ Section: ____________ Schedule: __________________________________ Date: ______________ The study of biopharmaceutics is based on fundamental scientific principles and experimental methodology. Studies in biopharmaceutics use both in vitro and in vivo methods. In vitro methods are procedures employing test apparatus and equipment without involving laboratory animals or humans. In vivo methods are more complex studies involving human subjects or laboratory animals.  These methods must be able to assess the impact of the physical and chemical properties of the drug, drug stability, and large-scale production of the drug and drug product on the biologic performance of the drug. Pharmacokinetics is the science of the kinetics of drug absorption, distribution, and elimination (i.e., metabolism and excretion). The description of drug distribution and elimination is often termed drug disposition. Characterization of drug disposition is an important prerequisite for determination or modification of dosing regimens for individuals and groups of patients. Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body; this includes the mechanisms of drug action and the relationship between drug concentration and effect. A typical example of pharmacodynamics is how a drug interacts quantitatively with a drug receptor to produce a response (effect). The pharmacodynamic effect, sometimes referred to as the pharmacologic effect, can be therapeutic and/or cause toxicity. Pharmacodynamics refers to the relationship between the drug concentration at the site of action (receptor) and pharmacologic response, including biochemical and physiologic effects that influence the interaction of drug with the receptor. The interaction of a drug molecule with a receptor causes the initiation of a sequence of molecular events resulting in a pharmacologic or toxic response. Receptors are the molecules that interact with specific drugs to produce a pharmacological effect in the body. Drug exposure refers to the dose (drug input to the body) and various measures of acute or integrated drug concentrations in plasma and other biological fluid Drug response refers to a direct measure of the pharmacologic effect of the drug. Figure 1-2 shows that the concentration of drug in the body can range from subtherapeutic to toxic. In contrast, some patients respond to drug treatment at lower drug doses that result in lower drug concentrations. Other patients may need higher drug concentrations to obtain a therapeutic effect, which requires higher drug doses. This document is the property of PHINMA EDUCATION  COURSE CODE:PHA068 (BIOPHARMACEUTICS AND PHARMACOKINETICS) STUDENT ACTIVITY SHEET MODULE #1 Name: _________________________________________________________ Class number: _______ Section: ____________ Schedule: __________________________________ Date: ______________ Pharmacogenetics is the study of drug effect including distribution and disposition due to genetic differences, which can affect individual responses to drugs, both in terms of therapeutic effect and adverse effects. It is desirable that adverse drug responses occur at drug concentrations higher relative to the therapeutic drug concentrations, but for many potent drugs, adverse effects can also occur close to the same drug concentrations as needed for the therapeutic effect. Other terms to remember: Clinical pharmacokinetics is the application of pharmacokinetic methods to drug therapy in patient care. Population pharmacokinetics is the study of pharmacokinetic differences of drugs in various population groups Toxicokinetics is the application of pharmacokinetic principles to the design, conduct, and interpretation of drug safety evaluation studies (Leal et al, 1993) and in validating dose-related exposure in animals.  Toxicokinetic data aid in the interpretation of toxicologic findings in animals and extrapolation of the resulting data to humans. Toxicokinetic studies are performed in animals during preclinical drug development and may continue after the drug has been tested in clinical trials Clinical toxicology is the study of adverse effects of drugs and toxic substances (poisons) in the body. LADME Scheme - describes the pharmacokinetic processes which follow a given dosage regimen Liberation- the release of the drug from the dosage form Absorption- The movement of the drug from the site of administration to the systemic circulation (bloodstream). Due to its anatomical structure, the organ which is the most important site of drug absorption is the small intestine. Distribution- The process by which drug diffuses or is transferred from intravascular space (systemic circulation/ bloodstream) to extravascular space (body tissues/ site of action) Metabolism (aka Biotransformation) The chemical conversion or transformation of drugs into compounds which are easier to eliminate. Liver is the principal site of drug metabolism. Excretion- The removal of unchanged drug from the body via renal, biliary, or pulmonary processes. Major pathway of excretion is via the kidney. Drug elimination is the sum of the processes of removing an administered drug from the body. It is frequently considered to encompass both metabolism and excretion This document is the property of PHINMA EDUCATION  COURSE CODE:PHA068 (BIOPHARMACEUTICS AND PHARMACOKINETICS) STUDENT ACTIVITY SHEET MODULE #1 Name: _________________________________________________________ Class number: _______ Section: ____________ Schedule: __________________________________ Date: ______________ Drug disposition is the description of drug distribution and elimination Three phases of drug action in the body: Pharmaceutic phase- disintegration or dissolution of the drug following administration. This process renders the drug into a form that can be used by the body. Pharmacokinetic phase- includes absorption, distribution, metabolism, and excretion of the drug Pharmacodynamic phase- drug interacts with drug receptors Although LADME processes generally follow the above sequence, these are not discrete events. That is, one process is still occurring while the next one begins. Each event continues to occur well into the next. In fact, all five processes may occur simultaneously. Consider the case of a sustained release drug, the core of the SR tablet may still be liberating drug while previously absorbed drug is being eliminated. LADME processes can be divided into two classes, drug input and drug output. Input processes are: Liberation and Absorption The term commonly used to describe the rate and extent of drug input is bioavailability. Drugs administered by intravenous routes exhibit essentially 100% bioavailability. Output processes, or disposition of drug are: Distribution, Metabolism and Excretion The LADMER system deals with the complex dynamic processes of liberation of an active ingredient from the dosage form, its absorption into systemic circulation, its distribution and metabolism in the body, the excretion of the drug from the body and the achievement of response. LADMER overview What happens to the active ingredient in the body after administration of a drug product in its various dosage forms? This entire cycle of processes is termed fate of drugs. This document is the property of PHINMA EDUCATION  COURSE CODE:PHA068 (BIOPHARMACEUTICS AND PHARMACOKINETICS) STUDENT ACTIVITY SHEET MODULE #1 Name: _________________________________________________________ Class number: _______ Section: ____________ Schedule: __________________________________ Date: ______________  The fate of drugs is described by the LADMER system, showing that liberation, absorption, distribution, metabolism, and elimination are involved to elicit the response.  A drug administered in a dosage form by any route of administration must be released from the dosage form (except IV, and true solutions for other routes). In order for a drug to be absorbed, it must be present in the form of solution; therefore, dissolution becomes the first and sometimes rate-limiting step. Upon administration of suspensions, capsules, tablets, suppositories, implants, and intramuscular (IM) suspensions, we find drug particles in the gastrointestinal (GI) tract, in body cavities, or in tissue. After dissolution, the drug diffuses to the site of absorption (e.g., buccal, sublingual, gastrointestinal, percutaneous, subcutaneous, intramuscular, intraperitoneal, intracutaneous, ocular, nasal, pulmonary, rectal). Liberation is the first step in determining onset of action, rate of absorption, bioavailability, and so on. This is true for all drug products by all routes of administration, except intravenous (IV) and the peroral use of true solutions. Liberation is controlled by the characteristics of the drug product.  Some of the drug will already be inactivated before it can be absorbed. Only drugs administered intravenously in solution enter the circulatory system immediately. With all other routes of administration, the drugs must pass membranes that act as lipid barriers. Different transport mechanisms are employed to penetrate into and to permeate through these membranes. Most of the drugs are absorbed or transported by passive diffusion, which depends on the pKa value of the drug, the pH of the solution, and the lipid solubility of the unionized form.  Drugs passing through the lipid barrier may directly enter the central compartment, i.e., after intramuscular, subcutaneous, intraperitoneal, intracutaneous, nasal, ocular, and pulmonary, and, partly, after rectal administration. Drugs administered perorally and some of the drugs administered rectally are confronted with enzymes as they pass through the liver with the blood flow. In the liver, the main place of metabolism, some drugs are inactivated and metabolized during the first pass; other drugs are activated here. Most drugs are at least partially bound to protein in the bloodstream. Only the free, unbound form of the drug is available for action. The protein-bound fraction is not permanently trapped but is in equilibrium and will be released from the protein as the free drug is eliminated from the plasma.  The drug may enter the peripheral compartment by again passing a lipid barrier until it finally reaches the biophase (process of distribution). This is a cell, or even a cell component, where the final interaction between drug and receptor takes place. After release of the drug from its receptor binding, the drug again passes through a lipid barrier and enters the central compartment, from which the drug, by again passing a lipid barrier, is metabolized in the liver or kidney or in the tissue or plasma. It then either passes via biliary excretion into the intestines or passes through the kidney, where it will be either reabsorbed or finally excreted into urine.  Elimination is not only by urinary and biliary means but also through the salivary glands, the milk glands, the sweat glands, and the lungs.  Reabsorption takes place not only in the kidney by tubular reabsorption but also in the intestine after enterohepatic cycling if the drug or its metabolite is in absorbable form. All these factors are involved in determining whether the drug administered will produce a therapeutic effect, yield only a subtherapeutic effect, or even show toxic effects. This document is the property of PHINMA EDUCATION  COURSE CODE:PHA068 (BIOPHARMACEUTICS AND PHARMACOKINETICS) STUDENT ACTIVITY SHEET MODULE #1 Name: _________________________________________________________ Class number: _______ Section: ____________ Schedule: __________________________________ Date: ______________  For most drug products, a relatively rapid and quantitative absorption and a slow elimination are required in order to maintain a therapeutic drug concentration for a long period of time. In some cases, this goal may easily be achieved: if the drug is soluble and highly unionized, is absorbed by passive diffusion, and has a long elimination half-life. If this is not the case, many manipulations are necessary to create a drug product with the desired characteristics. The LADMER system is key to the following tasks: Development of new active compounds, analogs, or derivatives; Development of dosage forms with desired release characteristics; Determination of pharmacokinetic parameters and pharmacokinetic drug product profiles; Determination and evaluation of bioavailability; Selection of the most appropriate route of administration; Determination of effective dose sizes; and Adjustment of dosage regimen to achieve a desired therapeutic concentration of drug in the body based on physiologic (e.g., body weight, age, sex) and pathologic (e.g., renal, hepatic, or heart failure; obesity; malnutrition) factors 2. Activity 3: Skill-building Activities (20 mins+ 5 mins checking) I. Modified True or False. Write TRUE if the statement is correct, but if it is FALSE change the underlined word or group of words to make the whole statement true. Check your answers against the Key to Corrections found at the end of this SAS. Write your score on your paper. ______________________1. Toxicokinetic studies are performed in humans during preclinical drug development ______________________2. Absorption is the release of the drug from the dosage form ______________________3. Pharmacologic effect can be therapeutic and/or cause toxicity ______________________4. Drug exposure refers to dose of drug input to the body ______________________5. Drug elimination involves both metabolism and excretion ______________________6. Pharmaceutic phase includes absorption, distribution, metabolism, and excretion of the drug ______________________7. In vivo methods are complex studies involving human subjects or laboratory animals ______________________8. Drug product or dosage form is a formulation of the drug with various excipients ______________________9. Pharmaceutics is the application of pharmacokinetic methods to drug therapy in patient care. _____________________10. Pharmacogenetics is the study of pharmacokinetic differences of drugs in various population groups _____________________11. Bioavailability refers to the percent or fraction of an administered dose of unchanged drug that reaches the systemic circulation _____________________12. The liver is the principal organ for drug excretion _____________________13. Once the drug is liberated from its dosage form it must be dissolved. _____________________14. The interaction of a drug molecule with a receptor causes the initiation of a sequence of molecular events resulting in a pharmacologic or toxic response _____________________15. A pharmacodynamic response results when the drug concentration at the site of action reaches or exceeds the minimum effective concentration. _____________________16. Characterization of drug disposition is an important prerequisite for This document is the property of PHINMA EDUCATION  COURSE CODE:PHA068 (BIOPHARMACEUTICS AND PHARMACOKINETICS) STUDENT ACTIVITY SHEET MODULE #1 Name: _________________________________________________________ Class number: _______ Section: ____________ Schedule: __________________________________ Date: ______________ determination or modification of dosing regimens for individuals and groups of patients. _____________________17. Bioavailability of drug administered through IV is 100% bioavailable because the drug is delivered directly into the systemic circulation _____________________18. Input processes includes disposition of the drug. _____________________19. Pharmacodynamics studies what the drug does to the body. _____________________20. Physical and chemical properties of the drug influence bioavailability of the drug 3. Activity 4: What I Know Chart, part 2 (5 mins) This serves as a review and summary of what you have learned from the session. Monitor how your knowledge has changed by reviewing the questions in the What I Know Chart from Activity 1 and write your answers to the questions based on what you now know in the third column of the chart. 4. Activity 5: Check for Understanding (10 mins). Answers will be provided by the instructor. A. Multiple Choice. Choose the letter of the correct answer. Write the capital letter of your answer before the number. 1. The LADMER system is employed in: a. The development of new active compounds b. The determination of effective dose c. The adjustment of dosage regimen d. All of the above 2. The first step which determines the onset of action, rate of absorption & bioavailability of the drug is: a. Liberation b. Distribution c. Excretion d. Absorption 3. In general, the form of the drug that can be absorbed faster is a. Ionized b. Unionized c. Bound form d. A & C 4. Refers to the sum processes of removing an administered drug from the body. a. Disposition b. Metabolism c. Excretion d. Elimination 5. The ff. is/are biopharmaceutic considerations in drug product design, except? I. Route of administration II. Physical and chemical properties of Active pharmaceutical ingredient III. Frequency of doses IV. Patient compliance a. I- III b. IV only c. III- IV d. None of the above 6. Study of mechanisms of drug action and the relationship between drug concentration and effect. This document is the property of PHINMA EDUCATION  COURSE CODE:PHA068 (BIOPHARMACEUTICS AND PHARMACOKINETICS) STUDENT ACTIVITY SHEET MODULE #1 Name: _________________________________________________________ Class number: _______ Section: ____________ Schedule: __________________________________ Date: ______________ a. Drug exposure b. Pharmacodynamics c. Biopharmaceutics d. Pharmacokinetics 7. The process of drug transfer from intravascular space to extravascular space a. Absorption b. Distribution c. Metabolism d. Excretion 8. The ff. is/are correctly paired, except? I. Pharmaceutic phase- renders the drug into a form that can be used by the body. II. Pharmacokinetic phase- absorption, distribution, metabolism, and excretion of the drug III. Pharmacodynamic phase- drug interaction with receptors a. I only b. II- III c. All of the above d. None of the above 9. Which of the ff. statement/s is/are correct? a. In vitro methods are procedures employing test apparatus and equipment without involving laboratory animals or humans. b. In vivo methods involve human subjects or laboratory animals c. All of the above d. None of the above 10. Reabsorption of the drug takes place in the a. Kidney b. Intestines c. All of the above d. None of the above C. LESSON WRAP-UP 1) Activity 6: Thinking about Learning (5 mins) A. Work Tracker You are done with this session! Let’s track your progress. Shade the session number you just completed. 1 2 3 4 5 6 7 8 9 10 B. Think about your Learning Which part of the topic was easy for you? This document is the property of PHINMA EDUCATION  COURSE CODE:PHA068 (BIOPHARMACEUTICS AND PHARMACOKINETICS) STUDENT ACTIVITY SHEET MODULE #1 Name: _________________________________________________________ Class number: _______ Section: ____________ Schedule: __________________________________ Date: ______________ Which part of the topic was difficult to understand? How did you study and comprehend hard topics of this module? Frequently Asked Questions (FAQs) Which is more closely related to drug response, the total drug dose administered or the concentration of the drug in the body? Drug dose administered is more closely related to drug response, because the suggested dosing regimen, including starting dose, maintenance dose, dosage form, and dosing interval, is determined in clinical trials to provide the drug concentrations that are therapeutically effective in most patients. Why do individualized dosing regimens need to be determined for some patients? Intra and inter individual variations (e.g. age, gender, genetic, and ethnic differences) will frequently result in either a sub therapeutic (drug concentration below the MEC) or toxic response (drug concentrations above the minimum toxic concentration, MTC), which may then require adjustment to the dosing regimen. Therefore; During the drug development process, large numbers of patients are tested by the manufacturer to determine optimum dosing regimens, which are then recommended in the package insert to produce the desired pharmacologic response in the majority of the anticipated patient population. Key to corrections Activity 3: Skill building activity 1. Animals 11. True 2. Liberation 12. Kidney 3. True 13. True 4. True 14. True 5. True 15. True 6. Pharmacokinetic 16. True 7. True 17. True 8. True 18. Output 9. True 19. True 10. Population pharmacokinetics 20. 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