Biopharmaceutics and Pharmacokinetics Foundations PDF

Compiled by Ritch Joshua Villadarez NOT FOR SALE BIOPHARMACEUTICS and PHARMACOKINETICS FOUNDATIONS 1 Compiled by Ritch Joshua Villadarez NOT FOR SALE PHARMACEUTICS...

Compiled by Ritch Joshua Villadarez NOT FOR SALE BIOPHARMACEUTICS and PHARMACOKINETICS FOUNDATIONS 1 Compiled by Ritch Joshua Villadarez NOT FOR SALE PHARMACEUTICS - Concerned with the formulation, manufacture, stability and effectiveness of the pharmaceutical dosage form - Drug product performance: release of the drug substance from the drug product for local drug action or for drug absorption into the plasma for systemic therapeutic activity BIOPHARMACEUTICS Definition - Interrelationship of the physicochemical properties of the drug, the dosage form, and the route of administration on the rate and extent of drug absorption (liberation to absorption) o can determine if the administered drug is therapeutically effective OR toxic OR has no apparent effect at all Bioavailability - Measure of systemic availability (rate and extent of absorption) of a drug - Basis for drug product design and development o Explain difference in drug effect o Explain generic drug controversy o Design drug delivery system Biopharmaceutic - Therapeutic objective considerations in drug - API product design - ROA - Drug dosage and dosage regimen (starting dose, maintenance dose, dosage form, dosing interval) - Type of drug product - Excipients - Method of manufacture Involvement - Design of the drug product - Stability of the drug within the drug product - Manuf of the drug product - Release of the drug from the drug product - Rate of dissolution/release of the drug at the absorption site - Delivery of drug to the site of action PHARMACOLOGY Definition - Study of drugs: its mechanism, effects and uses - Medicinal Chemistry/SAR + Pharmacokinetics + Pharmacodynamics PHARMACOKINETICS - Study of the time course of drug movement in the body during absorption, distribution, metabolism and excretion - “What the body does to the drug” o Input process: Liberation, Absorption o Output/Disposition: Distribution, Metabolism, Excretion o Elimination: Distribution, Metabolism, Excretion Experimental PK - Development of biologic sampling techniques, analytical methods for the measurement of drugs and metabolites and procedures that facilitate data collection and manipulation Theoretical PK - Development of pharmacokinetic models that predict drug disposition after drug administration Classical PK - Study of theoretical models focusing mostly on model development and parameterization Population PK - Study of the Pharmacokinetic differences of drugs in various population groups 2 Compiled by Ritch Joshua Villadarez NOT FOR SALE PHARMACODYNAMICS - Study of the biochemical and physiological effects of drugs in the body o MOA o Drug conc. And effect - “what the drug does to the body” - How a drug interacts quantitatively with a receptor to produce a response o Inc. dose = inc. drug conc. = inc. intensity of effect - It is desirable that the toxic effects occur at a higher drug conc. Than the drug conc. Needed for the therapeutic effect CLINICAL - Application of pharmacokinetic models/methods to drug therapy in patient care PHARMACOKINETICS - Age/ Gender/ Genetics/ Ethnicity => Pharmacokinetic differences => Differences on the outcome of drug therapy - Applied to Therapeutic Drug Monitoring for very potent drugs to optimize efficacy and prevent adverse effects o Monitor plasma drug conc. o Monitor specific pharmacodynamic endpoints PHARMACOGENETICS - study of variability in drug response due to heredity or differences in genes PHARMACOGENOMICS - study of the effect of the whole genome (complete set of genetic information/genes of a species) on drug response CLINICAL TOXICOLOGY - study of adverse effects of drugs and toxic substances in the body TOXICOKINETICS - application of pharmacokinetic principles to the design, conduct and interpretation of drug safety evaluation studies and in validating dose-related exposure MEASUREMENT of DRUG CONC to DRUG RESPONSE Background - recommended dosage regimen may not provide the desired therapeutic outcome due to individual differences - measurement of plasma drug conc, can confirm whether the drug dose was subtherapeutic due to individual pharmacokinetic profile or was not responsive due to genetic difference in receptor response Drug exposure - dose and various measures of acute or integrated drug conc. In plasma and other biological fluid Drug response - direct measure of pharmacologic effect of the drug o remote biomarkers o presumed mechanistic effect o potential or accepted surrogate o long-/short-term clinical effects Methods of Chromatography - separates the drug from other related materials that may cause assay Measurement interference Mass spectrometry - allows detection of molecules or fragments based on their mass-to-charge ratio Invasive Methods - acquisition of any biologic material via parenteral or surgical intervention Noninvasive Method Types of Biologic samples Via Blood, Plasma, - measuring drug conc. From samples of blood, plasma or serum is the most direct approach to Serum assessing pharmacokinetics of the drug in the body Whole blood - contains cells and proteins - it is allowed to clot and then serum is extracted after centrifugation Plasma - liquid supernatant after centrifugation of nonclotted whole blood - contains proteins but no cells Serum - liquid obtained after blood is clotted - without proteins - unbound drug conc.: drugs that are filtered from the plasma - bound drug conc.: unfiltered plasma Via Tissues - occasionally removed for diagnosis - since tissue removed is small, it is difficult to measure drug conc. With it - does not reflect drug conc. In other tissue nor in all parts of the organ due to differences in perfusion - used to ascertain if the drug reached the tissues and reached the proper conc. Within the tissue Via Urine and feces - indirect method - Urine: reflect the rate and extent of systemic drug absorption o cumulative urinary excretion Data: uses conc of metabolite in urine (can be inaccurate – not all drugs are excreted renally) - Feces: reflects the drug that has not been absorbed after oral dose o Reflects the drug that has been expelled by biliary excretion after systemic absorption Via saliva - Only free drug diffuses into the saliva - Saliva drug levels tend to approximate the free drug rather than the total plasma drug conc. - Drug conc. Ratio is affected by the pKa of the drug and the pH of saliva 3 Compiled by Ritch Joshua Villadarez NOT FOR SALE Plasma Drug - generated by obtaining drug conc. In plasma samples taken at various time intervals after the drug is Concentration – Time administered curve - absorption is more rapid than elimination o Flip flop PK: absorption is slower than elimination - as the drug is absorbed it is also distributed to all tissues and is also simultaneously eliminated - Minimum Effective concentration (MEC): minimum conc of drug needed at the receptors to produce the desired pharmacologic effect - Minimum toxic concentration: (minimum safety conc) drug conc needed to just barely produce a toxic effect - Onset time: time required for the drug to reach MEC - Intensity: Peak conc – MEC: proportional to the # of receptors occupied; higher plasma conc = greater pharmacological effect - Duration of Drug action: difference between the onset time and the last time point on the MEC - Therapeutic window: MTC – MEC - Therapeutic index: MTC/MEC (ratio) - The time for peak plasma level is the time of max drug conc. o A rough marker of average rate of drug absorption - Max drug conc is related to o Dose o Rate constant for absorption o Elimination constant - Area Under The Curve (AUC): amount of drug absorbed systemically Significance - Ascertains that the calculated dose delivers the plasma level required for therapeutic effect - Distinguished the patient who is receiving too much of a drug from one who is super sensitive to the drug predict pharmacodynamic response for drugs that act irreversibly at receptors - Pharmacokinetic models allow more accuracy in the interpretation of the relationship between plasma drug conc. And response Basic Pharmacokinetic Models Background - Drugs are in a dynamic state within the body - Biologic nature of drug distribution and disposition is complex and happens simultaneously - Models: a hypothesis using math terms to describe quantitative relationships quantitatively o Predictive capability of a model lies in the proper selection and development of mathematical functions that parametrizes the factors governing kinetic processes o Devised to simulate the rate processes of drug ADE to describe and predict drug conc. In the body as a function of time Objectives of 1. Predict plasma, tissue and urine drug levels with any drug dosage regimen Pharmacokinetic 2. Calculate the optimum dosage regimen for each patient individually Models 3. Estimate the possible accumulation of drugs and/or metabolites 4. Correlate drug conc. With pharmacological or toxicologic activity 5. Evaluate differences in the rate/extent of availability between formulations (bioequivalence) 6. Describe how changes in physiology or disease affect the absorption, distribution or elimination of the drug 7. Explain drug interactions Empirical model - Practical 4 Compiled by Ritch Joshua Villadarez NOT FOR SALE - Not very useful in explaining the mechanism of the drug’s ADE in the body Physiologically-Based - Depends on the spatial location of the tissue from the surrounding blood vessel that the tissue drug Models conc. Can differ or even on the type of cell involved o Perfusion o Since tissues are not homogenized, drug conc. May be estimated by knowing the tissue/organ extraction ratio based on the physiological and biochemical composition of body organs Compartmentally- - Describes the body as a tank with a volume of fluid that is rapidly equilibrated with the drug Based Models - Compartment: tissue/group of tissues that have similar blood flow and drug affinity o Hypothetical volume that contains a certain drug conc o Space or region on the body where you can locate the drug o Central compartment: compartment with the bloodstream o Peripheral compartment: others - Parameters: o The fluid volume of the tank that will dilute the drug o Elimination rate of drug per unit of time o For parameters to be valid, the number of data points must ALWAYS exceed the number of parameters in the model - Mixing of the drug within a compartment is rapid and homogenous so that the drug conc. Represents an average conc. And each drug molecule has an equal probability of leaving the compartment - Rate Constants: represent the overall rate processes of drug entry into and exit from the compartment - Open system: a model that presents that the drug conc. Can be eliminated from the system Mamillary model - A strongly connected system - One can estimate the amount of drug in any compartment of the system after drug is introduced into a given compartment - Has a central compartment Caternary Model - Consists of compartments joined together like compartments of a train (linear) Physiologic - Considers that blood flow is responsible for distributing drugs to various parts Pharmacokinetic of the body Model (Flow - Provides a better insight into how physiological factors may change drug model) distribution from one species to another 1. No data fitting is required 2. Physiological factors may vary due to pathophysiological conditions 3. Data may be extrapolated MATHEMATICAL FUNDAMENTALS Background - PK models consider drugs in the body to be in a dynamic state - Differential equations are used to relate the concentrations of drugs in various body organs over time - Integrated equations are used to model the cumulative therapeutic/toxic responses of drugs in the body Differential - Involves finding the rate at which variable quantity is changing Calculus 5 Compiled by Ritch Joshua Villadarez NOT FOR SALE - Noyes-Whitney equation: expressing the rate at which the drug dissolves by determining the rate of drug diffusing away from the surface of the solid drug Integral Calculus - Reverse of differentiation - Summation of f(x) X dx - Summation of the small individual pieces under the graph - Definite integral: sum of individual areas under the graph of that function - Trapezoidal rule: used to calculate AUC – the area between time intervals is the area of the trapezoid - The total area under the plasma drug level-time curve from time zero to time infinity is obtained by summation of each individual area between each pair of consecutive data points using the trapezoidal rule Graphs - X axis – time - Y axis – drug concentration - Semilogarithmic allows placement of the data at logarithmic intervals so that the numbers need not to be converted to their corresponding log values prior to plotting on the graph Curve Fitting - Implies that there is some sort of relationship between the variable x and y - Relationship is not confined to isolated points but is a continuous function of x and y - Physiologic variables are not always linearly related - However, the data may be arranged or transformed to express the relationship between the variables as a straight line - General equation of a straight line: Y = mx + b (m = slope; b = y intercept) o If m value is high = slope is steeper o m value is (-) = slope is downward o m value is (+) = slope is upward o m value is 0 = slope is horizontal Linear Regression/ - Used to construct a linear relationship between x and y Least squares - The relationship between plasma drug conc. Vs. time can be expressed as a linear function method o + m = positive linear relationship o – m = negative linear relationship - correlation coefficient (r): assesses the strength of the linear relationship o +r=+m o R = 1 = perfectly linear o M = 0, r = 0 = no relationship o R = < 0.95 = nonlinear o R = > 0.95 = linear o High correlation between two variables does not necessarily mean causation ▪ It is the distribution and elimination function that cause the level of drug to decrease overtime - Coefficient of determination (r2): expresses how much variability in the outcome is explained by the input factor o If r = 0.90, then r2 = 0.81, then there is 81% variability - Linear regression assumes that there is a linear relationship between variables - Interpolation: filling the gap between observed data on a graph - Extrapolation: predicting new data beyond the observed data Terms - Cmax – maximum drug conc. In plasma (rate and extent of absorption; most variable parameter) - Tmax – time to reach Cmax (rate of absorption) - Rate Constant – function of drug eliminated per unit of time - Half-life – time needed for 50% of the drug to be eliminated - AUC – extent of absorption from the site of administration - Mean residence time - (Tmax, Cmax) – max point on the curve; reflects the rate of absorption - Absolute BA: when the reference Route is IV 6 Compiled by Ritch Joshua Villadarez NOT FOR SALE - Relative BA: reference route is not IV - Log: logarithm to base 10 - Ln: natural logarithm, logarithm to base e - Ln x = 2.303 log x RATES and ORDERS of PROCESSES Zero order Process - Proceeds over time INDEPENDENT from the concentration of the drug - Fixed amount of drug is removed per unit time - Plasma conc vs Time o Half life is conc dependent o Rate is conc independent - Ex. Suspensions; Phenytoin, Phenylbutazone, Warfarin, Heparin, Ethanol, ASA/salicylates, Theophylline, Tolbutamine First order Process - DEPENDENT upon drug concentration - Fixed percentage of drug is removed per unit time - Natural log of Plasma conc vs time o t½ = ln2/K = constant and independent of initial drug conc. o rate is dependent of drug conc Zero Order Reaction First order Reaction Equation –dC/dt = k0 –dC/dt = kC Ct = –k0t + C0 logC = -k/2.303 + logC0 lnCt = –k0t + lnC0 Ct = C0e–kt Rate constant - units (mg/L)/h 1/h Half-life, t ½ (units = time) T ½ = 0.5C/k T ½ = 0.693/k T ½ = C/2k T ½ = ln2/k Not constant Constant Shelf life T90 = 0.1 (C) / k T90 = 0.105 / k Effect of time on rate Zero order rate is constant with respect First order rate will change with to time respect to time as concentration changes 7 Compiled by Ritch Joshua Villadarez NOT FOR SALE Effect of time on rate Rate constant with respect to time Rate constant remains constant with constant changes as the concentration changes respect to time Rectangular coordinate plot Drug concentration declines linearly Drug concentration declines nonlinearly Semilogarithmic graph Drug concentration declines Drug concentration declines linearly nonlinearly Linear Pharmacokinetics - First order reaction - AUC and steady state conc increases as dose increases Nonlinear - Elimination rate varies from first to zero order = “dose dependent PK” Pharmacokinetics - Saturation kinetics or capacity-limited metabolism o Salicylates, salicylamide, PABA, phenytoin, theophylline o Elimination of drug does not follow simple first-order kinetics = nonlinear o Elimination t ½ changes as dose changes; may increase but may also decrease due to self-induction of metabolism (carbamazepine) o AUC is not proportionate to the amount of bioavailable drug o Affected by competition o Composition and/or ratio of metabolites may be affected by dose changes - Michaelis-menten or Enzyme kinetics - Mediated by an enzyme present in limited amounts - Dosing is critical Flip flop kinetics - when the rate of absorption of a compound is significantly slower than its rate of elimination from the body - common for Class 3 and 4 BCS - ex. Penicillin G OVERVIEW of ROUTES of ADMINISTRATION - intravascular: IV, intraarterial, intracardiac - Extravascular o Enteral: oral, buccal, sublingual, rectal o Parenteral: SQ, IM, intrathecal o Others: inhalational, intranasal, ocular, vaginal, urethral ENTERAL ORAL - Into the oral cavity ✓ Cheap ✓ Convenient ✓ Variety X absorption may vary and erratic X slower absorption than IV/IM X inefficient X first pass effect, acid degradation, enzymatic metabolism by enterocytes X food X GI motility X not for local effect (except for insoluble luminal drugs) X unconscious/uncooperative patient 8 Compiled by Ritch Joshua Villadarez NOT FOR SALE BUCCAL/ - Buccal: buccal sulcus, under the cheek (for slow acting) SUBLINGUAL o Replaced by dermal patches - Sublingual: under the tongue (for fast acting) ✓ Rapid absorption, esp. for lipophilic drugs ✓ Minimal first pass effect ✓ Drug stability ✓ Local prolonged action X inconvenience X small doses, not for high dose drugs RECTAL - Into the rectum ✓ No first pass effect ✓ For children ✓ Local/systemic effect X erratic absorption O Inferior and middle hemorrhoidal vein: leads to common iliac vein → vena cava = no first pass effect O Superior HV: inferior mesenteric vein → hepatic portal vein → liver X not well accepted ENTERAL via - For patients unable to swallow medications nasogastric tube - May need extemporaneous compounding PARENTERAL SUBCUTANEOUS - Under the skin, 45˚ - For aqueous solution, slow absorption All bypass ✓ Self-administration, ex. insulin liberation ✓ Complete absorption X rate of absorption depends on blood flow and injection flow 100% BA: IV, X painful intraarterial, X tissue damage intracardiac X max dose of 20 mL for kids INTRAMUSCULAR - Into the muscle (deltoid, gluteus maximus, vastus lateralis), 90˚ - Rapid from aqueous solution - Slow from nonaqueous solution ✓ Larger volume ✓ Depot or sustained release effect ✓ Easier to inject than IV X trained personnel X erratic absorption X Painful, irritating INTRATHECAL - Directly into the spinal cord - Avoid blood brain barrier - Spinal anesthesia ✓ 100% absorption ✓ Direct injection into CSF for uptake into brain INTRADERMAL - Into the dermis (vascular region of the skin below the epidermis), 10-15˚ o For diagnostic and allergy test X discomfort INTRAARTICULAR - Into the joint space o Hyaluronic acid, corticosteroids for osteoarthritis o Morphine for knee surgery INTRAPERITONEAL - Absorption resembles in oral o For small lab animals o For peritoneal dialysis INTRAVENOUS - into peripheral vein, 25˚ ✓ rapid ✓ total dose ✓ insensitive x difficult x maybe toxic x trained professional x expensive x tissue damage IV Bolus - 100% systemic absorption - Instantaneous BA rate ✓ Immediate effects X inc. adverse reaction/anaphylaxis risk IV Infusion - 100% systemic absorption 9 Compiled by Ritch Joshua Villadarez NOT FOR SALE - Controlled drug absorption rate by infusion rate ✓ Large fluid volumes ✓ Drugs with poor lipid solubility and irritating ✓ Controlled plasma drug levels X skilled personnel only X tissue damage INTRAARTERIAL - into the artery - high drug concentration in a specific drug distribution occurs throughout the body - for diagnostic agent and cancer chemotherapy X may distribute to other organs INTRACARDIAC - into the heart chamber (heart muscles and ventricles) - for life threatening conditions o ex. Streptokinase for myocardial infarctions miscellaneous INHALATIONAL - Drug is inhaled per orally (with a nebulizer or metered-dose aerosol) into the pulmonary tree - Lung pH = 7.4 - Absorption of gasses is relatively efficient - Local (bronchodilators) or systemic (general anesthesia) ✓ Lung has the greatest surface area ✓ Rapid absorption ✓ Bypass the liver X cough reflex (due to mucociliary clearance) X some drugs may be swallowed - Factors that affect deposition of drugs in the lungs o Physicochemical properties o Formulation o Technique (depth of inspiration, pause prior to exhalation) o Pulmonary tree - >60 microns – trachea - > 20 microns – do not reach bronchioles - < 6 microns – reach the alveolar ducts but only 1.2 microns are left - < 0.6 microns – not deposited and are exhaled - 3-5 mcg – OPTIMAL - < 3 mcg – easily exhaled - Large particles are deposited in upper airways TOPICAL - Local effects - Absorption through the skin TRANSDERMAL/ - Placement of a drug, usually as a patch for systemic absorption PERCUTANEOUS - Slow to varied absorption rate - Inc. absorption with occlusive dressing ✓ Easy to use ✓ For small lipophilic, low dose or low MW drugs ✓ No first pass X irritation X Varied permeability of skin X Drug release depends on base - Factors that affect percutaneous absorption o Site of application o Condition of the skin o Hydration of skin o Temperature o vehicle INTRANASAL - into the nasal cavity - has local and systemic effects o for propranolol and some low dose hormones - factors that influence absorption from the nasal mucosa o pH o concentration o molecular weight o formulation o condition of the nasal mucosa ✓ rich in blood vessels X drug can be swallowed X surfactants are added to inc. penetration but can be irritating 10 Compiled by Ritch Joshua Villadarez NOT FOR SALE X drugs must be small molecules with balanced lipophilicity /hydrophilicity VAGINAL/ - for infections URETHRAL o ex. Clindamycin, sulfanilamide LIBERATION of DOSAGE FORMS Liberation - process of API release from dosage form - only biopharmaceutical process – conversion to aqueous solution form o true solutions are exempted – syrups, elixirs - highly modifiable process via drug product and delivery system formulation Disintegration - When absent/slow = slow liberation = dec. absorption and - Disintegrants: swells with gastric fluid => disintegration Dissolution - Solubility: static property in a saturated solution - Dissolution: dynamic (time course) property related to rate of absorption - Aqueous solubility (hydro/lipo) o Crystalline form o Particle size ▪ Micronization of poorly soluble drugs o Salt formation Particle size - Low particle size = high surface area = inc dissolution rate - Solution > suspension > capsule > tablet - Current rifampicin is micronized - Noyes-whitney Partition coefficient - Ratio of drug solubility in nonaqueous solvent (n-octanol) to that in an aqueous solvent (water, pH 7.4 buffer solution) - PC = Co/Cw o High PC = inc lipophilicity Extent of ionization - Dependent on the pKa of weak electrolyte and the pH of the solution/environment - Henderson-Hasselbalch equation: relationship between the ionized and nonionized species of a weak electrolyte Polymorphism - Ability of a drug to exist in more than one crystalline form - Polymorphs have different physical properties (MP, BP, dissolution rate, etc) - Amorphous > crystalline; anhydrous > hydrous o Amorphous insulin, rapid absorption IM/SC o Crystalline insulin, for long duration o 70% crystalline + 30% amorphous for intermediate action Complex formation - Reversible/irreversible association of 2 or more molecules or ions o Tetracycline + Ca/Milk = less water-soluble complex = dec Absorption o Theophylline + ethylenediamine = aminophylline = 5x more water- soluble = inc absorption o Cyclodextrin + drug = water soluble complexes = inc absorption o Drug-protein complex = do not cross cell membranes easily Salt formation - More stable and more soluble drug forms Chirality Hydrates Formulation - Inert ingredients that assist in the manuf of the dosage form or to impart certain Excipients properties to the finished product o Lubricant: inc. pourability o Diluents: inc. size of the dosage form to a manageable size o Wetting agents 11 Compiled by Ritch Joshua Villadarez NOT FOR SALE o Dissolution enhancers o Permeation enhancers - Liberation o Attrition o Disintegration: no palpable core ▪ state in which any residue of the unit, except fragments of insoluble coating or capsule shell, remaining on the screen of the test apparatus or adhering to the lower surface of the disk, if used, is a soft mass having no palpably firm core. o deaggregation - Dissolution - Convection and diffusion - absorption Rate-limiting step - Slowest step in drug release o Conventional oral dosage forms: dissolution o Modified-release forms: liberation Comparative Rates of Drug Absorption Oral Dosage Forms Parenteral 1. Aqueous solutions 1. Aqueous solutions 2. O/W emulsion 2. O/W emulsion 3. Oily solution 3. Oily solution 4. Suspension/Soft gel capsule 4. Suspension 5. Hard gel Capsules 5. Pellets 6. Uncoated Tablets 7. Coated tablets 8. Modified release tablets DRUG ABSORPTION Definition - Process of drug entry into the systemic circulation Factors affecting - physicochemical properties of the drug systemic absorption - nature of the drug product - anatomy and physiology of the drug absorption site (perfusion, pathophysiologic condition) Importance of - drug distribution and clearance are affected by Route of Drug o pathology administration o genetic polymorphism o drug-drug interaction X drug formulation - many drugs are not administered orally due to insufficient absorption from GIT o drug instability o degradation by digestive enzymes o inc. hepatic clearance and efflux transporters - some orally taken drugs are not intended for systemic activity - highly lipophilic drugs are subject to high first pass effects if swallowed - biotechnology-derived drugs are too labile in the GIT - burns increase the permeability of drugs across the skin DRUG TRANSPORT SYSTEMS Nature of Cell - factors affecting drug permeability Membranes o structure and properties of the drug o physical and biochemical properties of the cell membrane - membranes act as boundary between cells and interstitial fluids o semipermeable: water, lipophilic molecules and selected small molecules can pass but not ionized and large molecules - Transcellular absorption: across a cell - Paracellular absorption: through gaps or tight junctions between cells (slow, for molecules with MW = 500 or lower) - Lipid Bilayer/Unit Membrane Theory o By Davson and Danielli o Plasma membrane is composed of 2 layers of phospholipid between 2 surface layers of proteins, with the hydrophilic head facing the protein layers and the hydrophobic tail aligned in the interior ▪ Lipid soluble drugs penetrate cell membranes more easily ▪ Does not account the diffusion of water, Small MW molecules and some ions ▪ Drugs must be LMW, in solution (water soluble), nonpolar and nonionized - Fluid mosaic model: cell membrane consists of globular proteins embedded in a dynamic, fluid, lipid bilayer matrix 12 Compiled by Ritch Joshua Villadarez NOT FOR SALE o By Singer and Nicolson o These proteins provide a pathway for the selective transfer of certain polar molecules and charged ions o Modified fluid mosaic: These proteins function as structural anchors, receptors, ion channels or transporters Passive Diffusion - Molecules in solution spontaneously diffuse from area of high conc. To low conc. - No external energy is expended = SLOWEST (driven by conc gradient/difference) - For LMW, lipophilic (nonpolar, nonionized) drugs in aqueous solution wherein the membrane is not a barrier to diffusion and absorption o Weak electrolytes, water, urea - Forward moving drug molecules are balanced by molecules moving back = no net transfer of drugs o Flux: rate of transfer - Tendency of molecule to move in all directions is natural since molecules possess kinetic energy and constantly collide with each other - Major absorption process = 80% of drugs o Skin, mouth, stomach, small intestine, large intestine, rectum o Driven by high drug conc. on the mucosal side (conc gradient) Fick’s Law of Diffusion - describes the relationship between the rate of diffusion and the three factors that affect diffusion - 'the rate of diffusion is proportional to both the surface area (A) and concentration difference (CGI - Cp) and is inversely proportional to the thickness (h) of the membrane' o Duodenum = inc. Surface area = high A o Capillaries in the brain are densely lined with glial cells = slow diffusion o LUNGS: organ with greatest absorption (highest SA and blood supply) - Diffusion coefficient (D): amount of drug that diffuses across a membrane of a given area per unit of time when the conc. Gradient is unity o Property of the drug in relation to the property of the membrane ▪ Particle size (rifampicin – 2 to 10 microns) ▪ Lipophilicity Ionization Partition coefficient (K) Henderson-Hasselbalch equation - Extent of ionization influences the drug’s diffusional permeability o Depends on drug’s pKa and pH of medium - For electrolytes, the total drug conc. At both sides are not equal at equilibrium if the pH of the medium varies - Weak acids: HA (nonionized) → H+ + A- o Low Ka = high pKa = fast absorption o Best absorbed in stomach - Weak base: BH+ → H+ + B (nonionized) o High Ka = Low pKa = fast absorption pH-partition hypothesis - if pH of one side of a membrane differs from the pH of the other side, then: o the drug will ionize to different degrees on respective sides of the membrane o the total drug conc. On either side will be unequal o the compartment in which the drug is more highly ionized = inc. total conc. Carrier-mediated - uses carrier proteins to move molecules along the membrane Transport - selective, competitive, saturable o active carrier: against conc gradient = needs ATP o facilitated carrier: along conc gradient = no ATP - follows Michaelis Menten equation = zero order kinetics - example: o enterocytes – simple columnar epithelium that lines the intestines ▪ uptake transporters: influx => inc. drug conc. ▪ Efflux transporter: dec. systemic drug absorption ▪ Contains metabolizing enzymes = presystemic drug metabolism o Isoniazid and Pyridoxine Active Transport - Carrier-mediated and transmembrane transport - Transports drugs in aqueous solution against conc gradient (low to high) - Energy-consuming; requires a carrier that shuttles the drug across the membrane - Carrier can be highly selective and structurally substrate can compete o Saturable in high conc 13 Compiled by Ritch Joshua Villadarez NOT FOR SALE - Fastest transport system - Example o P-glycoprotein (Multidrug resistance transporter 1) ▪ Energy-dependent membrane protein; efflux transporter ▪ Found in intestines, BBB, liver, kidney ▪ Efflux transporters limit drug penetration to reduce drug accumulation (protective) - Found in stomach and small intestine - For polar molecules, glucose, AA, Na, K, I, B vitamins, pyrimidine bases, testosterone, estradiol, Fe, Ca - Competitive inhibition o CN, F, I2, acetate. 5-FU Facilitated Diffusion - Carrier-mediated system following the concentration gradient - No energy input - Saturable and shows competition kinetics for structurally similar drugs - Transport of Vit B12 - Occurs in small intestines Transporters - Present at the intestinal brush border and basolateral membrane for absorption of ions and nutrients - Uptake transporter o ATP-Binding cassette o Solute Carrier o Intestinal oligopeptide transporter/ di- or tripeptide transporter - Efflux transporter o MDR1/P-gp ▪ Gene symbol ABCB1 ▪ Highly expressed on the apical surface of superficial columnar epithelial cells in ileum and colon ▪ Dec. expression when reaching upper GIT Major sites: adrenal medulla, kidney medulla, colon, liver ▪ Protection against lipophilic and cytotoxic xenobiotics ▪ Triggered by cancer cells - Bidirectional drug transport: depends on which regard to a drug at a given site o Breast cancer resistance protein (BCRP) ABC G2 ▪ Against anti-CA, statins, nitrofurantoin, sulfated metabolites - Example PACLITAXEL DOCETAXEL - Activates pregnane X receptor - No pregnane X (induces intestinal excretion and receptor = inc. hepatic drug inactivation) absorption - Inc. MDRI transcription and PGp expression - Inc. CYP3A4 and CYP2C8 transcription - 85% excreted into GIT Vesicular Transport - Process of engulfing particles or dissolved materials by the cell; energy requiring - Envagenation of a cell membrane o Exocytosis: into the cell o Endocytosis: out to the cell ▪ Pinocytosis: cell drinking Corpuscular or particulate absorption via micelles Engulfment of small solutes or fluid volumes (macropinosome) Griseofulvin, ADEK, fats, starch, glycerin Small intestine, large intestine, rectum 14 Compiled by Ritch Joshua Villadarez NOT FOR SALE Does not need the molecules to be in solution = EMULSION form ▪ Phagocytosis: cell eating Engulfment of larger particles (phagosomes) Used by macrophages in immune system o Transcytosis: macromolecules transported across the cell interior - Vesicle fuses with membrane to release encapsulated materials to another side of the cell - Caveolae: tiny incuppings in cell surface that close and pinch off to form pinosomes which are free of cytosol - Proposed uptake of Sabin polio vaccine Pore/ Convective - Has channels/pores that permit entry of very small molecules (via transendothelial channels) transport - Aka pore or paracellular transport - “transport protein” - For small molecules, chainlike molecules, inorganic/organic molecules, esp small electrolytes o Pore size/diameter: 7-10 angstrom – allows MW hepatic portal vein => liver Gastrointestinal pH - Determines extent of ionization and where Weak acid Weak base drugs are best absorbed pH < pKa Unionized Ionized pH > pKa Ionized Unionized 16 Compiled by Ritch Joshua Villadarez NOT FOR SALE - pKa: pH of which 50% of the drug is ionized (50% is unionized) o pKa = 5.3 ▪ pH 5.3 = unionized = ionized ▪ pH 2 = unionized > ionized ▪ pH 8 = ionized > unionized Gastrointestinal - Tends to move the drug motility - Drug transit time depends on o Physicochemical properties of the drug o Pharmacological properties of the drug o Dosage form o Physiology o Presence of food - Migrating motor complex: propulsive movement that empties upper GIT to the cecum in fasted/interdigestive state - Housekeeper waves: irregular then regular contractions with inc. amplitude that pushes any residual contents - If fed, irregular contractions mix intestinal contents and moves it toward the colon Gastric Emptying - Time it takes for the stomach to empty its contents Time - Inc. GET = dec GE Rate = dec. absorption o Penicillin: unstable in stomach acid o Aspirin: increases gastric pH = irritating - Liquids and small particles (< 1 mm) are not retained in the stomach o Due to slightly higher basal pressure in the stomach over the duodenum - Large particles are delayed from emptying for 3-6 hours due to presence of food - Indigestible food empty very slowly during the interdigestive phase -in which food is absent and stomach is less motile Inc GET / Dec GER / SLOW Dec GET / Inc GER / FAST High CHON/Fat food Spicy foods Cold food Hot foods Gastric ulcers, Gastrectomy Aggression Depression Mild Exercise Vigorous exercise (stomach has less blood flow) Lying on the right side; standing Lying on the left side Anticonstipation, metoclopramide, domperidone, Antidiarrheals, antimotility agents, anticholinergics, cisapride narcotics, analgesic Diabetes Mellitus (lowers incretin), Hyperthyroidism Hunger, Parkinson’s, Stress, Ulcers Intestinal Motility - Drugs must have sufficient residence time at the absorption site for optimum, absorption - Inc motility = dec. Residence Time = Dec. Absorption o Normal Small intestine Transit Time (SITT) = 7 hours o Faster SITT = 4-8 hours o Fed state SITT = 8-12 hours (longer) - For modified-release or controlled-release dosage forms, they must within a certain segment of the small intestine to release the drug before excretion - Dietary fiber: retains water and bacterial mass => inc. fecal weight GIT Perfusion - Splanchnic circulation: receive 28% of the cardiac output and is increased after meals - High perfusion helps maintain concentration gradient, favoring absorption - Drug enters the small intestine, then absorbed into the mesenteric vessels then to the hepatic portal vein, then to the liver o Dec. mesenteric blood flow = dec. drug removal rate = dec. BA rate o CHF = dec mesenteric flow Lymphatic - Lipophilic drugs may be absorbed through the lacteal or lymphatic vessels under the microvilli Absorption - Bypasses liver: lymphatic vessels deliver directly to the vena cava - Lipophilic drugs (ex. Bleomycin, aclarubicin) are first dissolved in chylomicrons before entering lymphatic circulation Effect of Food - Chemicals in food can affect intestinal pH and drug solubility o Dec. gastric emptying rate o Inc. bile flow o Change in GIT pH o Inc. splanchnic blood flow o Change in luminal metabolism o Drug-food interaction - Inc. calorie meals =inc. alteration in GI physiology = inc. effects on BA o Penicillin, tetracycline, erythromycin - Lipophilic drug + high fat meal = inc. absorption o Griseofulvin, acarbose + fatty food = inc absorption 17 Compiled by Ritch Joshua Villadarez NOT FOR SALE o Cinnarizine, lovastatin + food = inc Absorption - Fasted state + water = inc. absorption o Sufficient water is necessary for drug dissolution - Drugs that are irritating to the GI mucosa are given with food to decrease irritation o Dec. absorption rate, not the degree of absorption and efficacy o Presence of food = dec. gastric emptying = affects absorption of enteric coated tablets o Fine granules (< 1-2 mm) and disintegrating tablets are not delayed in the presence of food o Food can also affect the integrity of the dosage form = altered release rate ▪ Dose dumping o Timing of drug administration is important ▪ 1 hour before; 2 hours after meals ▪ When eating fatty meals – 3 hours after o Fluid volume: distends stomach, inc. gastric emptying ▪ Inc. calorie = dec. Gastric emptying DECREASED Absorption with Food Doxycycline - Complexes with milk - DOC for primary stage of Lyme disease in adults and children older than 8 years old - Potential first line agent in the prophylaxis of anthrax after exposure - Popular choice for patients with preexisting renal disease or those who are at risk for renal insufficiency - Oral tetracycline of choice - Preferred parenteral tetracycline HMG-CoA Reductase - Pravastatin (Pravachol) blockers - Lovastatin (Mevacor) - Simvastatin (Zocor) - Fluvastatin (Lescol) - Atorvastatin (Lipitor) - Rosuvastatin - Taken once daily at bedtime/ in the evening (peak time for cholesterol synthesis) Clopidogrel - Inhibitor of platelet activation and aggregation through irreversible binding of its active metabolite to P2Y12 class of ADP receptors on platelets - Prodrug - + food = low amount of active metabolite Naproxen - Propionic acid derivative NSAID - Inhibits COX1 and COX2 => inhibits prostaglandins and thromboxane synthesis - + food = inc residence time = inc Tmax Alendronate - Bisphosphonates: prevents osteoclast from breaking down bones - Treatment of osteoporosis and Paget’s disease of bone - Taken atleast 30 minutes before first food/beverage intake Tamsulosin - a1 selective blocker for hypertension - higher BA in fasted conditions INCREASED Absorption with Food Oxycodone - narcotic analgesic; moderate agonism - 1.4 – 2x more potent than morphine - No significant active metabolites - Higher Cmax with high fat meal Metaxalone - Muscle relaxant: blocks nerve impulses in the brain - Higher Cmax and AUC with high fat meal Spironolactone - K-sparing diuretic, aldosterone blocker - X aldosterone = high Na/water secretion = diuresis - DOC for hepatic cirrhosis - High affinity for steroid hormones=> S/E: gynecomastia, impotence, BPH NO EFFECT on Absorption with Food Gabapentin - 2nd gen antiepileptic - GABA analog but does not bind to GABA-A receptors - 2nd line for partial seizures with or without secondary generalization - S/E: somnolence, dizziness, ataxia, fatigue - Slight increase in AUC and Cmax with food Tramadol - Oral, centrally-acting analgesic with weak opioid activity - For moderate to moderately severe pain - Food has no effect on rate and extent of absorption Digoxin - Cardiac glycoside from Digitalis lanata - Inhibits HF with atrial fibrillation - A/E: cardiac arrhythmia, anorexia, N/V, headache, fatigue, blurred vision - May increase the resting membrane potential = easily excitable= high risk of arrhythmia 18 Compiled by Ritch Joshua Villadarez NOT FOR SALE - Rate of absorption is slowed with food - Low amount absorbed with high bran fiber Bupropion - Norepinephrine/Dopamine reuptake blocker - For major depressive disorder and smoking cessation - Food has no effect Methylphenidate - Indirect adrenergic agonist - DOC for ADHD - Food has no effect; no dose dumping Fluoxetine - Selective 5HT reuptake inhibitor - Inc 5HT => for Major depressive disorder, obsessive-compulsive disorder, obesity, eating disorder - Well orally absorbed - High protein binding = high t ½ - Food delays absorption but no effect on BA Dutasteride - Oral antiandrogen - Treatment of symptoms of enlarged prostate - Low Cmax with food but not significant Double peak - Obtained after administration of a single dose to fasted patients phenomenon - Caused by: o Varied gastric emptying o Varied intestinal motility o With food o Enterohepatic recycling o Failure of a tablet dosage form ▪ A tablet that does not disintegrate (or incompletely) may have delayed gastric emptying 2nd absorption peak Effect of Diseases, Drugs and Nutrients DISEASES Induces changes in: - Intestinal blood flow - GI motility - Changes in Gastric emptying time - Gastric pH (affects solubility) - Intestinal pH (extent of ionization) - Gut wall permeability - Bile secretion - Digestive enzyme secretion - Alteration of GI flora Advanced - Difficulty in swallowing parkinson’s - Diminished GI motility disease Tricyclics/ - Anticholinergic effects Antipsychotic - Decreased GI motility therapy - Intestinal obstructions - Delays absorption of slow-release drugs Achlorhydria/ PPI - Decreased gastric acid = increased pH therapy - No formation of soluble salts of weak bases = undissolved and unabsorbed - Coadministration of acidic drinks = inc. absorption HIV-AIDS - Prone to GI disturbances - Rapid gastric acid time - Diarrhea Congestive Heart - Decreased splanchnic blood flow Failure with - Edema in bowel wall Persistent Edema - Dec. intestinal motility = dec. absorption Crohn’s disease - Inflammation of the distal small intestine to the colon - Thickening of bowel wall + overgrowth of anaerobic bacteria + obstruction of bowel = dec. absorption o Except propranolol Celiac disease - Inflammation of proximal small intestine - Sensitization to gluten - Inc. Gastric emptying rate - Inc. intestinal permeability Hypoxemia, - Affects microvilli Hypovolemia 19 Compiled by Ritch Joshua Villadarez NOT FOR SALE DRUGS Anticholinergics - Dec. stomach acid secretion - Propantheline bromide o Dec. gastric emptying o Dec. intestinal motility - Tricyclics/ Phenothiazines Metoclopramide - Prokinetic drug - Inc. gastric contraction - Relaxes pyloric sphincter - Inc. intestinal peristalsis - Dec. absorption time Antacids - + Cimetidine = inc. pH - + tetracycline, ciprofloxacin, = dec. absorption - Should be taken 2-6 hours before drug administration PPIs - Dec. acid secretion - Inc. pH - Interferes with some drugs and enteric coated drugs o Inc. pH degradation Cholestyramine - Nonabsorbable ion exchange resin - Treatment for hyperlipidemia - Binds to warfarin, thyroxine, loperamide = dec. absorption NUTRIENTS Calcium - Calcium absorption is an active process = facilitated by vitamin D - + vit D = inc. calcium binding protein - Binds calcium = transfer to blood stream Grapefruit juice - Inhibits CYP3A4 - Inc. BA of CYP3A4 substrates - Contains naringin (flavonoid), bergamottin (furanocoumarin) = inhibits CYP3A4 - Blocks efflux of P-gp Pharmacokinetics of Drug Absorption Bioavailability (BA - Rate or extent to which a drug substance gets absorbed and becomes available at the site of action or F) - Fraction of administered dose of unchanged drug that reaches the systemic circulation o In IV, dose administered = dose absorbed o In Extravascular, dose administered =/= dose absorbed o Absorbed dose = dose taken x BA o BA = AUC/Dose Absolute BA (Fabs) - True fraction of administered dose that reaches the systemic circulation - IV vs EV - Values are between 0 to 1 - Fabs of IV = 100% - Fabs of EV < 100% 𝑨𝑼𝑪 𝒐𝒇 𝒔𝒂𝒎𝒑𝒍𝒆 𝑩𝑨 𝒐𝒇 𝒕𝒆𝒔𝒕 𝒔𝒂𝒎𝒑𝒍𝒆 𝑫𝒐𝒔𝒆 𝒐𝒇 𝒔𝒂𝒎𝒑𝒍𝒆 𝑨𝒃𝒔𝒐𝒍𝒖𝒕𝒆 𝑭 = = 𝑩𝑨 𝒐𝒇 𝑰𝑽 𝒓𝒆𝒇𝒆𝒓𝒆𝒏𝒄𝒆 𝑨𝑼𝑪 𝒐𝒇 𝑰𝑽 𝒅𝒓𝒖𝒈 𝒓𝒆𝒇𝒆𝒓𝒆𝒏𝒄𝒆 𝑫𝒐𝒔𝒆 𝒐𝒇 𝑰𝑽 𝒅𝒓𝒖𝒈 𝒓𝒆𝒇𝒆𝒓𝒆𝒏𝒄𝒆 𝑨𝑼𝑪 𝒐𝒇 𝒔𝒂𝒎𝒑𝒍𝒆 𝑫𝒐𝒔𝒆 𝒐𝒇 𝒔𝒂𝒎𝒑𝒍𝒆 𝑭𝒂𝒃𝒔 = 𝒙 𝑫𝒐𝒔𝒆 𝒐𝒇 𝒔𝒕𝒂𝒏𝒅𝒂𝒓𝒅 𝑫𝒐𝒔𝒆 𝒐𝒇 𝒔𝒕𝒂𝒏𝒅𝒂𝒓𝒅 Relative BA (Frel) - BA of a certain drug relative to a second drug that contain the same moiety - Ratio of the Fabs of different products of the same drug substance - Values can exceed zero 𝑨𝑼𝑪 𝒐𝒇 𝒅𝒓𝒖𝒈 𝟏 𝑩𝑨 𝒐𝒇 𝑫𝒓𝒖𝒈 𝟏 𝑫𝒐𝒔𝒆 𝒐𝒇 𝑫𝒓𝒖𝒈 𝟏 𝑹𝒆𝒍𝒂𝒕𝒊𝒗𝒆 𝑭 = = 𝑩𝑨 𝒐𝒇 𝑫𝒓𝒖𝒈 𝟐 𝑨𝑼𝑪 𝒐𝒇 𝒅𝒓𝒖𝒈 𝟐 𝑫𝒐𝒔𝒆 𝒐𝒇 𝒅𝒓𝒖𝒈 𝟐 Bioequivalence - Same BA after administration of same dose and magnitude of their effects (safety and efficacy) - The drug present in two or more identical dosage forms reaches the systemic circulation o At the same relative rate o Same relative degree - Based on these parameters o Cmax: intensity (rate and extent) of absorption ▪ Most variable parameter o Tmax: rate of absorption o AUC: extent of absorption ▪ Reflects the total amount of active drug ▪ Most important parameter ▪ Computed using trapezoidal rule - 2 drugs are bioequivalent if ratio is between 0.8-1.25 (80-125%) 20 Compiled by Ritch Joshua Villadarez NOT FOR SALE Drug concentration - Administered drug does have a remarkable tendency to reach the systemic circulation, giving rise to the – Time graph attainable drug conc. In plasma to a max level - Absorption of a drug is found to be more fast and rapid vis-à-vis its elimination phenomenon (except for drugs with flip-flop kinetics) - After absorption, the drug eventually gets distributed to most tissues in the body and undergoes elimination simultaneously - Elimination may be via Excretion, biotransformation or both - MEC: actual conc. Of drug which would give a bare minimum level of effects if the drug in plasma = drug in tissues o Minimum conc. Of drug required at the receptor to exhibit the expected pharmacologic effect - MTC: prevailing drug conc. Required to cause a bare minimum extent of toxic effects - Intensity: proportional to the number of drug receptors occupied o Inc. plasma drug conc. = inc. response up to a max degree - Duration of action: difference between the onset time and the time it taken for the drug to decline back to the MEC - Factors guiding AUC o Absorption phase o Post-absorption phase o Elimination phase - Peak plasma conc is dependent on the o Dose o Rate constant for absorption o Elimination constant Physiological Factors modifying Bioavailability Adverse effects pH - Stimulated by gastrin and histamine within the GI lumen - Fed state: 1.5 - Fasted state: 2-6 - Natural penicillins are weak to acid hydrolysis o Penicillin G = most acid labile o Penicillin V = should be taken on empty stomach (lower pH than fed state) o Amoxicillin = more resistant - Acid labile drugs + antacids o Ex. Didanosine (reverse transcriptase blocker) - H2 blockers/PPI/ antacid + itraconazole/ketoconazole => dec. absorption - PPI + Ca = dec. absorption => icn. Risk for bone damage Enzymatic - Pepsin, trypsin, chymotrypsin inactivates insulin when taken orally attack - Enzymes of microflora o Important for conjugated drugs Enterohepatic - Reabsorption of a conjugated drug after its hydrolysis circulation - Leads to 2nd peak phenomenon o Ethinyl estradiol is conjugated in the liver, then excreted in the bile; when it passes the colon, the bacteria hydrolyze it then it will be reabsorbed ▪ Dec. absorption with antibiotics Interaction - Tetracycline + di-/trivalent ions = insoluble complex with Drugs - Antacids = ionizes acidic drugs Interaction - Food delays gastric emptying with Food o Altered GI pH o Inc. bile flow o Inc. liver blood flow o Dec. diffusion, dec. absorption o Chelation, dec. absorption o Inc. dissolution, inc. acidic degradation Transcellular - Driven by concentration gradient passive diffusion - Small intestines: high surface area, high perfusion = inc. concentration gradient = inc. absorption - Low Gastric emptying rate = slow absorption - Permeability = lipophilicity (determined by partition coefficient) - High molecular weight = low penetration, esp. < 500 da ✓ < 400 da Paracellular passive - Into the tight junctions between cells diffusion - For small molecules Transporters Uptake - Increases absorption of substrates Transporters - OATP1A2: substrates = fexofenadine, saquinavir o Inhibitor: grapefruit, apple, orange 21 Compiled by Ritch Joshua Villadarez NOT FOR SALE - OATP2B1: substrates = statins - PEPT1: di/tripeptides o Cephalosporins, penicillins, ACE inhibitors, valacyclovir Efflux - Dec. absorption of substrates Transporters - Pgp: cyclosporine, tacrolimus, paclitaxel, irinotecan, digoxin, talinolol - Substrates may saturate Pgp = dec. efflux = inc. BA - Dependent on high solubility, high lipophilicity o Diltiazem, verapamil Presystemic - CYP isozymes, glucuronosyl-transferase, alcohol dehydrogenase Intestinal - A fraction of the dose may be lost that is substantial Metabolism - CYP3A4 – 80% - CYP2C9 – 15% - Inhibitors: ketoconazole/itraconazole, macrolides, cyclosporine - Grapefruit juice: inhibits intestinal CYP3A4 (effects is conc. dependent) Presystemic - Intestines => mesenteric => hepatic portal system => liver Hepatic - First pass effect: ability of liver enzymes to metabolize a specific drug Metabolism - Hepatic extraction ratio: fraction of the incoming drug that is metabolized during a single pass through the liver - Hepatic BA: fraction of the dose entering the liver that escapes extraction Bioavailability and Bioequivalence of Drugs Evaluation of BA - Statistical analysis is used to evaluate results of BA studies Studies o No statistical difference – ANOVA and paired t-test - Range: 80 – 125% - Absorption rate constant: o Rate constant that described the overall absorption process o Even given that patient-related factors are constant, Ka is not a constant per drug o Affected by ▪ Formulation factors ▪ Route of administration ▪ Type of dosage form o High Ka = faster drug absorption Generic drugs - same active ingredients and the same labeled strength - same dosage form, same administration, same packaging - bioequivalent with the innovator drug essentially the same labeling as the innovator drug (Tmax, Cmax, AUC are 80-125%) o should be therapeutically equivalent with the innovator drug o AUC ratio: AUC of generic/ AUC of reference o Tmax ratio: Tmax of generic/ Tmax of reference o Cmax ratio: Cmax of generic/ Cmax of reference - full documentation of the drug's chemistry, manufacturing steps, and quality control measures - raw materials and finished product meet standard specifications - remain potent and unchanged until the expiration date - comply with GMP regulations GENERIC - dispensing a different brand or unbranded drug product in pla