PSW 313: Biopharmaceutics/Pharmacokinetics Lecture Notes PDF

PSW 313: BIOPHARMACEUTICS/ PHARMACOKINETICS Dr. G. Acquaah-Mensah Lecture 1 Introduction to Biopharmaceutics and Pharmacokinetics 1  Objectives To identify the place of pharmacokinetics in pharmacotherapy To defin...

PSW 313: BIOPHARMACEUTICS/ PHARMACOKINETICS Dr. G. Acquaah-Mensah Lecture 1 Introduction to Biopharmaceutics and Pharmacokinetics 1  Objectives To identify the place of pharmacokinetics in pharmacotherapy To define terms associated with pharmacokinetics, biopharmaceutics, and pharmacodynamics To discuss various approaches to assaying biological specimens To explain models used in pharmacokinetics To distinguish between various model types used in pharmacokinetics 23 3  Overview To Introduce and Define Concepts To Discuss Assays in Pharmacokinetics To Discuss Models in Pharmacokinetics 4 Introductory Chart Drug Dose administered Disintegration/Dissolution PHARMACEUTICAL PHASE Pharmaceutical Availability Absorption Distribution PHARMACOKINETIC Metabolism PHASE Excretion Pharmacological Availability Drug-Target PHARMACODYNAMIC Interaction PHASE Effect 5  Biopharmaceutics The study of the relationship between the nature and intensity of the biological effects AND the physicochemical properties of the drug Some authorities include Pharmacokinetics as a branch of Biopharmaceutics 6  Biopharmaceutics (Continued) Factors of interest influence: 1. Drug stability 2. Drug release rate-product 3. Dissolution / release rate- absorption site 4. Systemic absorption 7  Biopharmaceutics (Continued) Some formulation properties of interest: -type of dosage form - pharmaceutical process used in preparing it - presence (or absence) of adjuncts - physical state - particle size and surface area - chemical nature (salt, complex, ester, etc…) 8  Pharmacokinetics pharmakon (drug) and kinetikos (motion) Math analyses of ADME time courses The science of the kinetics of absorption, distribution and elimination of drugs relationship between drug administration, the time-course of its distribution and the concentrations attained in different regions 9 Parameters of Interest Amount of Drug Administered Rate constant for absorption Amount of Drug In Body Rate constant for elimination Amount of Drug Eliminated 10  Pharmacokinetics: Experimental Aspects Development of biologic sampling techniques Development of assay methods for drugs and metabolites Development of data collection and manipulation techniques 11  Pharmacokinetics: Theoretical Aspects Models that predict drug disposition following drug administration Classical pharmacokinetics: model development and parameter estimation 12  Pharmacokinetics: Clinical Aspects Patient-specific considerations Optimized dosing strategies Therapeutic drug monitoring (“TDM”) for drugs with narrow therapeutic index Population Pharmacokinetics: age, gender, ethnic, genetic considerations 13 Relationship of drug concentrations to drug response. 14  Toxicokinetics application of pharmacokinetic principles to toxicology Applied to the interpretation of pre-clinical toxicity data and their extrapolation to humans Non-linear pharmacokinetics at toxic doses – saturation of enzymes and other molecules involved in processes 15  Pharmacodynamics relationship between drug concentration at site of action and the pharmacologic response “What the drug does to the body” 16  DRUG CONCENTRATION ASSAYS Biological specimens Blood Concentrations Significance of Plasma Concentrations Plasma Concentration-Time Curve Tissue Concentrations Other Body Fluid Concentrations Assays have application in Therapeutics and Forensic Science 17  DRUG CONCENTRATION ASSAYS: Obtaining Biological Specimens Invasive methods involve parenteral or surgical intervention. Samples obtained by invasive methods include blood, spinal fluid, tissue biopsy, and synovial fluid Samples obtained by non-invasive methods include saliva, milk, urine, feces, and expired air 18  DRUG CONCENTRATION ASSAYS: Some Assay Types Chromatography: (e.g. HPLC separates drug from other substances) Immunoassays e.g. fluorescence immunoassays Radioactive assays (e.g. the TCA-RA assay for serum lidamycin) Mass Spectroscopy 19  DRUG CONCENTRATION ASSAYS: Data Obtained from Biological Specimens Pharmacologic or toxicologic outcome of drug dosing Metabolite formation Amount of drug transported into tissue or region 20  DRUG CONCENTRATION ASSAYS: Blood Concentrations Whole Blood: contains cellular elements and proteins Serum: supernatant obtained after centrifuging coagulated whole blood Plasma: supernatant obtained after centrifuging non-coagulated whole blood  PLASMA CONCENTRATION-TIME COURSE AFTER ORAL ADMINISTRATION Minimum Toxic Peak Concentration Concentration Plasma Drug Concentration Intensity Minimum Effective duration Concentration AUC Onset of Peak Action Time 22 Time PLASMA CONCENTRATION-TIME COURSE The AUC is a measure of the amount of drug the patient has been exposed to AUC useful in toxicity profile studies AUC useful in bioequivalence studies  DRUG CONCENTRATION ASSAYS: Plasma Concentrations Useful for optimization of individual dosage Other relevant pharmacokinetic information is needed in order to use plasma concentrations beneficially Pharmacodynamic response sometimes more important than plasma drug levels e.g. INR for anti-coagulants and ECG for cardiotonic drugs 24  DRUG CONCENTRATION ASSAYS: Tissue Concentrations Biopsies: small tissue samples removed on rare occasions for diagnostic purposes Disadvantage: blood flow and drug concentrations not uniform within tissues 25  DRUG CONCENTRATION ASSAYS: Urine and Fecal Concentrations Urine concentration of drug is an indirect indication of the systemic concentration of the drug Fecal drug concentration indicates lack of absorption after oral dose administration, or biliary secretion after systemic absorption 26  DRUG CONCENTRATION ASSAYS: Saliva Concentrations Approximates to free drug in plasma because free drug freely diffuses into saliva When taken after equilibrium with plasma drug concentrations, provides a good indication of free drug levels in body (weak acids and weak bases have good correlations to plasma drug levels) 27  Some Pharmacokinetic Concepts Model Pharmacokinetic parameter Pharmacokinetic Functions and prediction 28 Some Pharmacokinetic Concepts: Model A construct that uses mathematical terms to describe quantitative relationships. A model may be used to: 1. predict drug concentrations over time 2. optimize dosage regimen for individual patient 3. correlate drug concentration with effects 4. estimate possible accumulation of drugs/ metabolites 5. evaluate bioequivalences 6. explain drug interactions 7. describe how physiology or disease affects drug ADME 29 Some Pharmacokinetic Concepts: Pharmacokinetic Parameter A constant for a given drug determined from experimental data Value depends on – model used – method and timing of sampling – method of analysis 30  Pharmacokinetic Parameter (continued) E.g. – VD (the volume within which the drug is distributed), – ke (governs the rate at which the drug concentration decreases over time) – t1/2 (the time needed for the quantity of a drug to be reduced by one-half), etc…. 31 Some Pharmacokinetic Concepts: Pharmacokinetic Functions Relationship between an independent variable and a dependent variable i.e. using pharmacokinetic parameters Can be used to describe and predict drug concentrations in the body over time 32  Model Types Physiologically-based models Empirical (Compartment-based) models 33  Physiologic Models Also called Blood Flow Models OR Perfusion Models i.e. blood flow is the means by which a drug is distributed to various tissues Based on actual anatomical and physiological data e.g. known tissue volume is used rather than an estimated Volume of Distribution 34  Compartment Models A compartment is a tissue or tissue group that has similar blood flow and drug affinity, rather than a physiological or anatomical region. **Mammillary Model **Catenary Model 35  Compartment Models II Features: -Linear assumptions -Use of rate constants for both drug entry and exit -Open system -following introduction of drug into a compartment, drug concentrations in other compartments of the system may be estimated 36  Mammillary Model: One Compartment System Drug is added to and eliminated from a central compartment (plasma and highly perfused tissues such as liver and kidney) ke Intravenous drug injection CENTRAL COMPARTMENT Following first order Drug absorption ka ke CENTRAL COMPARTMENT 37  Mammillary Model: Two Compartment System Central compartment plus tissue compartment CENTRAL TISSUE COMPARTMENT COMPARTMENT ke 38  Catenary Model Multiple tissue compartments connected to each other and the central compartment like a train TISSUE COM- TISSUE COM- CENTRAL TISSUE COM- PARTMENT III PARTMENT II COMPARTMENT PARTMENT I ke 2390  MODEL TYPES CONTRASTED PHYSIOLOGICAL COMPARTMENTAL MODEL MODEL Drug concentrations predicted from Data fitting required tissue size, blood flow, blood drug concentrations and tissue drug concentrations Pathophysiological conditions influence Pathophysiological conditions influence data and therefore the model data and therefore the model Animal data (from several species) Extrapolation not possible because Vd may be used to predict human data by is only a mathematical construct and extrapolation has a less exact relationship to blood flow and volume Experimental data required for this is Difficult to obtain data not required practically difficult to obtain Predict realistic tissue drug Limited in this regard concentrations 40