Pharmaceutics 11 PDF

Pharmaceutics 11  Terms Drug - includes any substance or mixture of substances manutactured, sold or represented for use in — (a) the diagnosis, treatment, mitigation or prevention of a disease, disorder, abnormal physical state, or the symptoms the...

Pharmaceutics 11  Terms Drug - includes any substance or mixture of substances manutactured, sold or represented for use in — (a) the diagnosis, treatment, mitigation or prevention of a disease, disorder, abnormal physical state, or the symptoms thereof, in man Biopharmaceutics or animal; or the study of the relationships between the physical (b) restoring, correcting or modifying organic and chemical properties, and its activity in the living functions in man or animal body. Dosage form- Pharmaceutical dosage form can Bioavailability be defined as a physical form of a drug such as a Bioavailability is the fraction of drug that reaches the solid, liquid or gas by which it can be delivered systemic circulation in proper form to particular sites within the Bioavailability for IV = 1 (straight into circulation) body. Bioavailability for oral < 1 Example: tablets, capsules, powders, oral (First pass effect) solutions, injectable solutions Drug product performance- the release of the drug substance from the drug product leading to bioavailability of the drug substance. It involves drug release, drug absorption and drug action. Pharmacokinetics- the study of how the body Bioequivalence interacts with administered substances for the Compares bioavailability study of two or more entire duration of exposure. Pharmacokinetics is formulations of the same drug. what the body does to the drug. It involves absorption, distribution, metabolism, and excretion of drugs. Narrow therapeutic Pharmacodynamics- what the drug does to the Drugs: body. It studies a drug's molecular, biochemical, warfarin and physiologic effects or actions. It comes from (blood thinner) the Greek words "pharmakon," meaning "drug," Phenytoin and "dynamikos," meaning "power." (Control seizure) Carbamazepine (Treat epilepsy, Pharmacogenetics- the branch of pharmacology mixed episodes in concerned with the effect of genetic factors on bipolar 1 disorder) reactions to drugs. It is the study of how our Vancomycin genes affect the way we respond to medications. (Antibiotic) Note: method of manufacture is different for eg/ 50ml and 100ml Toxicology Albumin- protein in blood The science of severe effects of drugs or Systemic absorption- increase drug absorption chemicals. It is the scientific study of adverse Drug product= api and excipients (affects how product is going to work) effects that occur in living organisms due to The orange book- to determine if a generic form of a drug is available to chemicals. fill prescriptions. Identifies the application of holder of a drug and does not identify distributors. Approved prescription drug products with therapeutic equivalence evaluation  Introduction to Biopharmaceutics Biopharmaceutic and Drug Product Design Content: Therapeutic indication Factors affecting Drug Design API Drug Absorption Routes of Administration Cell Membranes Route of administration Transport mechanisms Drug dosage and dosage regimen Drug Product Design Type of drug product Site Excipients Systemic drug absorption Method of manufacture Indication Measurement of Drug Concentration Systemic Absorption Factors Drug concentration in the body related more to - Physiochemical properties of the drug drug response than amount of drug administered - Nature of the drug product Drug Concentration measured in biological Anatomy of absorption site samples Physiology of the absorption site Sampling - invasive or non-invasive methods Analytical methods - differentiate between protein Bioavailability Factors bound or unbound parent drug and each metabolite Rate and extent of absorption: Most direct approach - measure drug / metabolite The release of the drug in blood, serum or plasma Permeability of the drug Degradation performed before arriving at the systemic Blood Components circulation (blood) Biopharmaceutics and Drug Design Scientists: >Biopharmaceutics - drug and drug product >Factors - physiologic and pathologic Pharmacists: >Understand relationship of drug dosage form to efficacy / ADRs/ interactions Plasma Drug Concentration-Time Curve ADME Interrelationship Therapeutic window vs therapeutic index Plasma Concentration vs Time From the following figure. Calculate: The MEC. The MTC. The therapeutic window (between MEC and MTC The onset of action (The time at which the plasma concentration equals the MEC). The duration of action (the length of time for which the drug remains above the MEC) The intensity of action (the height of plasma TI= Td50/ concentration between the MEC and the maximum Ed50 (ratio) plasma concentration. Cmax, & Tmax, Extent of absorption= area under the curve Drug Absorption Continued Table: Route of Administration Route of Administration Systemic availability and onset of drug action: Blood flow Physiochemical characteristics (drug and its product) Distribution and clearance: Pathology Drug-drug interactions Genetics Insufficient Systemic Absorption (GIT) - Drug stability in GIT Drug degradation (digestive enzymes) High hepatic clearance (first-pass effect) Efflux transporters (pull ions back in) These factors result in poor or erratic systemic drug availability. Drugs Given for Local Activity Oral drugs administered for local action and not systemic absorption include: Cholestyramine (Questran®) cholesterol Mesalamine (Pentasa® or Asacol®) crohn’s High first-pass effect if given orally: Nitroglycerin (transdermal patch, sublingual, inhalation) Fentanyl (transdermal patch) Route of Drug Administration Biotechnology derived drugs - parenteral (too labile in GIT): E.g. erythropoietin and human growth hormone (somatropin) given im Insulin (im and sc) Extravascular route of administration, the drug must first be absorbed, transported to site of action to acquire biological/therapeutic outcome Cell Membranes Plasma Membrane Models - Systemic absorption cross cellular membranes Thin: 70 - 100 Angstroms in thickness Oral administration, drug molecules cross the intestinal epithelium via Cell membrane: Mainly Phospholipids (bilayer different processes to reach the systemic circulation with carbohydrates and protein groups) Movement of the Drug Molecules Theories: Permeability of the drug at the absorption site into the blood is affected by: Lipid bilayer or unit membrane theory (Davson Structure and properties of the drug and Danielli, 1952) Physical and biochemical properties of the cell membrane [Lipid soluble drugs penetrate easier than polar drugs] Transcellular absorption - process of drug movement across a cell Fluid Mosaic Model (Singer and Nicolson, 1972) Transport Processes/Mechanisms Paracellular Drug Diffusion - gaps Plasma Membrane (Fluid Mosaic Model) Transcellular Transport pass through cell membrane Passive Diffusion - Diffusion form a region of high concentration to a region of low concentration Rate of transfer is called flux Major absorption process for most drugs Driving force is higher drug concentrations Drug Absorption Continued Enterocytes Fick's Law of Diffusion Simple columnar epithelial cells Fick's First Law Lines intestinal walls Movement of particles (diffusion flux) from high to Drug transporters low concentration is directly proportional to the Tight junctions particle's concentration gradient Drug metabolizing enzymes Fick's Law of Diffusion Factors that can influence the rate of drug absorption: - Lipid-water partition (drug-membrane) Surface area (membrane) Thickness (membrane) Diffusion coefficient (drug) Henderson-Hasselbach Equation Drug Transport Extent of ionization of a weak electrolyte: Passive Diffusion: does not require the cell to expend any pka of the drug energy and involves a substance diffusing down its pH of the medium concentration gradient across a membrane. Factors Affecting Bioavailability Carrier-mediated transport: refers to transport mediated by - First pass hepatic metabolism a membrane carrier protein. Solubility of the drug Nature of the drug formulation Vesicular transport: the processes of moving molecules across cellular membranes using vesicles. Absorption of Drugs Transport of drug from the GIT: Pore (Convective) transport: responsible for the Passive Diffusion, Active Transport, Exo (Endo)cytosis transportation of drug molecules via the protein channels Effect of pH on drug absorption: Henderson-Hasselbach into the cell. (the flux developed due to the motion per se of Eqn, pH=-log|H+] the bulk fluid) Physical factors influencing absorption: Blood flow to site, Surface area of site, Contact time at lon-pair formation: the process of creating electrically the absorption surface neutral complexes from oppositely charged ions, and then moving them across membranes Paracellular drug absorption (500MW): The process of drug absorption that occurs between the epithelial cells rather than through them, influenced by tight junction integrity. Drug Absorption Continued lon-Pair Formation Strong electrolyes (highly ionized or charged molecules Carrier-Mediated Transport lon-pair = ionized drug + opposite charge ion = neutral overall Active transport: directly uses a source of chemical charge, hence, diffuses easily energy (eg, ATP) to move molecules across a membrane against their gradient. Drug Interactions in GIT Facilitated Diffusion Many common drugs and certain foods are substrates for both the efflux transporters and CYP3A enzymes (e.g. Active Transport dextromethorphan, HBr, grapefruit juice) Carrier-mediated trans-membrane process Grapefruit juice affects drug transport in the intestinal wall Against concentration gradient Certain components of grapefruit juice - flavonoids (naringin Requires a carrier molecule and bergamottin) inhibit P-gp and CYP3A, hence increase Similar structure drugs - compete bioavailability of dextromethorphan results Saturation (high concentration) Drug Interactions in GIT Cont'd Carrier-Mediated Transport Esomeprazole and omeprazole inhibit gastric acid resulting in P-gp (MDR1): increased gastric pH Energy dependent Increase in pH can affect (decrease) absorption of drugs that Membrane bound require a gastric pH (ketoconazole, iron salts) Efflux transporter Defense mechanism - drug accumulation Intestinal Enzymes and Transporters Facilitated Diffusion Carrier-mediated transport Moves along a concentration gradient (high to low) No energy to be included Structurally selective Saturable Competes - similar structure drugs Oral Drug Absorption Minimal role in drug absorption Oral dosage form created to: Withstand extreme pH changes Intestinal Transporters Presence or absence of food Uptake/Influx transporters - promotes absorption Degradative enzymes Efflux transporters - hinders absorption Varying drug permeability in different regions of the intestine Motility of the GIT Genetics and Transporters Main genetic Superfamilies: Anatomy and Physiology of GIT ATP-binding cassettes (ABC) Normal physiology processes of the GIT is affected by: Diet Solute carrier (SLC) GIT contents PEPT1 (PepT1) - proton/peptide co-transporter. Hormones (SLC15A1) (uptake transporter) Visceral nervous system MDR1 (P-gp) - ABCB1 Disease BCRP - ABCG2 Drugs/drug formulation properties Vesicular Transport Enteral System Process of engulfing particles or dissolved materials Mouth to anus by the cell Major physiologic processes in the GIT: Pinocytosis - engulfment of small solutes or fluids Secretion Phagocytosis - engulfment of larger particles or Digestion macromolecules Absorption Endocytosis/exocytosis are the processes of moving specific macromolecules Pore (Convective) Transport Crossing of very small molecules (urea, water) of cell membranes Transport protein - forms open channel (via diffusion) Drug Absorption Continued Factors Affecting Stomach pH Physiologic Processes The transport of substances to the lumen of the alimentary canal - secretion Enzymes (saliva) and pancreatic secretions The breakdown of food constituents into smaller structures - Digestion Most absorption occurs in the duodenum The transport of the constituents from the lumen to the body Increased pH: interaction with enteric coated drug products (blood) - absorption Few fat-soluble, acid stable drugs may be absorbed from the Drugs pass areas of the enteral canal: stomach (passive diffusion) Oral cavity Ethanol rapidly absorbed, in the fasting state compared to fed, Oesophagus in the stomach Other parts of GIT Residues exit the body via feces (anus) Duodenum Total transit time = 0.4 to 5 days Common Duct: from pancreas and gallbladder Transit time includes: pH: 6-6.5 Gastric emptying Pancreatic juices (from bile duct) contains enzymes Small intestinal transit (3-4 hours healthy Trypsin, chymotrypsin and carboxypeptidase: hydrolysis of Colonic transit proteins to AA Amylase: digestion of CHOs Fluid along the alimentary canal Pancreatic lipase: hydrolyzes fats and fatty acids Small intestines: digestive juices and liquids Site of Passive diffusion: high SA and blood flow Colon: fluid reabsorbed, hence area less moist Lack of solubilizing effect of the chyme and digestive fluid Jejunum contributes to less favourable Middle portion of small intestine (between duodenum and ileum) Parts of the Enteral System Digestion of protein and CHOs after adding pancreatic juice Oral Cavity: and bile Saliva main secretion (pH = 7) Fewer contractions than duodenum Saliva: 1500mL secreted per day This portion preferred for in vivo drug absorption studies Saliva contents: ptyalin (salivary amylase) Mucin (glycoprotein), lubricates food Ileum Mucin secreted to interact with drugs Terminal part of small intestines Used for buccal absorption of lipid-soluble drugs Fewer contractions than the duodenum Dosage forms: sL, ODTs, Perfused for drug absorption studies pH; 7 (distal part pH = 8) Esophagus Acid drugs dissolve in ileum (bicarbonate secretion present) Connects the pharynx and the cardiac orifice of the stomach Bile secretion helps dissolve fats and hydrophobic drugs Fluid pH: 5-6 Lower part ends with esophageal sphincter Colon Very little drug dissolution occurs in this area pH:5.5-7 Lacks villi: Low SA Stomach Limited drug absorption: low SA, lacks blood flow; lacks the Innervated by vagus nerve more viscous and semisolid nature of the lumen contents Nerve plexus, hormones, mechanoreceptors sensitive to Lined with mucin that functions as lubricant and protectant stretch of Gl wall Drugs dissolved in this area good candidates for oral sustained Chemoreceptors control regulation of gastric secretions, release dosage forms including acid and stomach emptying Aerobic and anaerobic microorganisms: may metabolize some pH (fasting 1-2.5; fed 5) drugs Parietal cells secrete stomach acid stimulated by gastrin and Mesalamine acts locally in this area in Crohn's disease histamine Gastrin released from G cells (antral mucosa and duodenum) Rectum Gastrin release regulated by stomach distention (swelling) and Length:15cm peptides, amino acid. End at anus Intrinsic factor enhances B12 absorption In absence of fecal material: limited fluid (2mL) Gastric enzymes e.g pepsin (digestion) No buffer capacity: dissolving drug/excipient can have an Basic drugs solubilized rapidly in stomach acid (antral part) effect on the pH: 7 Antral milling - process of breaking down large particles Perfused by superior, middle and inferior (closest to the anal Pyloic sphincter opened to empty food and liquid in duodenum sphincter) hemorrhoidal veins Fatty acids, mono-and diglycerides (high density foods) delay Avoids hepatic first pass effect gastric emptying Absorption depends on position of suppository Drug Absorption Continued Perfusion of the GIT Factors Affecting Drug Absorption in the GIT Large network of capillaries and lymphatic vessels Drugs absorbed by passive diffusion from all parts of the perfuse the duodenal region and peritoneum alimentary canal, especially the duodenum The splanchnic circulation receives 28% of the cardiac output and increased after meals Factors: Maintain concentration gradient (high perfusion) Gastrointestinal Motility Decrease in mesenteric blood flow (CHF), decreases rate Gastric emptying time of drug removal from intestinal tract - result in decreased Intestinal motility rate of drug bioavailability Perfusion of GIT Absorption through the lymphatic system Effect of food Presystemic metabolism in intestine and liver Gastrointestinal Motility This moves the drug through alimentary canal; hence, drug may not remain at absorption site Transit time depends on physiochemical and pharmacologic Absorption through the lymphatic System properties of the drug Lipophilic drugs may be absorbed through lacteal or Type of dosage form and various physiologic factors lymphatic vessels under the microvilli Fasted or fed? Absorption of drugs via the lymphatic system bypasses the liver (avoids first-pass effect) Motility Patterns in the Interdigestive (Fasted) Lymphatic vessels drain into the vena cav rather than the and Digestive (Fed) State hepatic-portal vein Effect of Food on GI Drug Absorption Intestinal pH and solubility of drugs are affected by digested food contents (amino acids, fatty acids, other nutrients) Effects of food on bioavailability of drug: Delay in gastric emptying Stimulation of bile flow Change in pH of GIT Increase in splanchnic drug flow Gastric Emptying Time Change in luminal metabolism of the drug substance Delay in gastric emptying of the drug will delay the rate Physical or chemical interaction of the meal with the drug and maybe the extent of drug absorption - result in longer product or drug substance onset time Time meal was taken Penicillin unstable in acid, delay in emptying can degrade Nutrient and caloric content of a meal the drug in the stomach Meal volume or volume of water taken with drug Aspirin - delay in gastric emptying can result in gastric Meal temperature irritation - prolonged contact Enteric coated and nondisintegrating formulations are delay in gastric emptying to duodenum Factors That Affect Gastric Emptying Time Certain size granules not significantly delayed (1-2mm) Consumption of meals high in fat Dose dumping Cold beverages Anticholinergic drugs Effect of Food on Drugs' Bioavailability Large particles (incl tabs) delayed from emptying for 3-6 hours by the presence of food in the stomach Indigestible solids empty very slowly Intestinal Motility Normal peristaltic movement mixes the contents in duodenum Drug must have a sufficient time at absorption site for optimum absorption (residence time) Disease - diarrhea? MR/CR dosage forms Transit time (mouth to anus) - 53.3 hours (radio-opaque marker) Drug Absorption Continued Rule of Five This rule predicts that poor drug absorption or permeation is more likely when: There are more than five hydrogen-bond donors There are more than 10 H-bond acceptors The molecular weight is greater than 500 Da The calculated log P (ClogP)^2 is greater than 5 (or Mlog P>4,15) Methods for Studying Factors That Affect Drug Absorption Biorelevant Drug Dissolution Studies (drug release) High fat, better absorption Gamma Scintigraphy (site of drug release) Markers to study effect of gastric and Gl transit time Note: dose dumping- dose not released as should (slow released preparation) due to presence of eg alcohol, all dose is released at once pH differs in diabetes pH < pKa to the left Exists as [HA] / [BH+] pH > pKa to the right More water, better dissolution of Exists as [B] / [A-] drug Distribution of drug is more ionized Questions: 1. Explain the physiological processes 2. Draw, label and explain enterocytes 3. Drug metabolizing enzymes 4. List and describe transport mechanisms 5. Describe types of intestinal transport and give examples of influx (SLC) and eg flux (PGP, ABCs) 6. Explain drug interaction with example 7. List factors that can affect normal processes of the GI tract 8. How does fat increase affect bioavailability of drug 9. What is onset time (time to reach minimum effective Presystemic Metabolism in the Intestine and concentration Liver 10. How does water affect bioavailability of drug (dissolution) Absolute oral Bioavailability (F) is determined by various 11. Describe factors affecting drug absorption (liver; more factors: blood flow, intestine; large surface area Drug's solubility and permeability (extent) 12. Anatomy of the area Fraction of dose escaping intestine and liver extraction/ 13. Gastric motility operating after time (quiet to contractions) metabolism is Fg and Fh respectively 14. Intestinal motility Fa = extent to which drug gets absorbed 15. Describe secretion, absorption, digestion Absolute oral Bioavailability (F) = F * Fg* Fh 16. define duration of therapeutic window and index 17. Define pore transport Question A given drug is completely absorbed but extensively metabolised by the intestinal epithelium (91%) followed by extensive hepatic extraction (71%). What is the expected overall oral bioavailability? F= F x Fg x Fh = 1 x (100-91/100) x (100-71/100) = 2.61% Introduction to pharmacokinics ACCUMULATION Inverse of elimination Accumulation factor = 1/Fraction loss in one dosing CONTENTS interval Definition of pharmacokinetics Wash out period- giving body Dose-effect relationship enough time to eliminate drug out of system (by 1/2 life) 5 or more 1/2 Clearance lives Volume of distribution Half life Bioavailability Maintenance/Loading doses PHARMACOKINETICS VOLUME OF DISTRIBUTION Deals with how drugs are handled by the body This is an apparent volume that relates dose to plasma The study of the time course of drug absorption, distribution, concentration metabolism and excretion (ADME) Va = Amount of drug in body/Conc'n of Higher- most drug in extra vascular space unbound drug in blood/plasma Not true space related to drug being in the area Elimination encompass metabolism and excretion Distribution- Pulling from blood then eliminate- need to redistribute Some going to Therapeutic effect and adverse effects Equilibrium vs direct arrow- Breaking down Getting rid of Adverse effects Administration, goes into extra vascular vol, an equilibrium would be established, distribution, no clearance All administered into beaker, no clearance/ escape only administration Leaking out, being administered, decrease, Increase then decrease because escapes PHYSIOLOGIC/PATHOLOGIC Administration, distribution, slower decline because 2 beakers, clearance Similar in which it reaches equilibrium PROCESSES Physiologic processes - body size (changes in body) BIOAVAILABILITY Pathologic processes - HF, renal failure (diseases) Bioavailability is the fraction of unchanged drug reaching the PK parameters systemic circulation following administration by any route Dose adjustments Bioavailability for IV = 1 Bioavailability for oral < 1 PHARMACOKINETIC PARAMETERS ER = CL (liver) /Q; F= f * (1 - ER) Blood flow Extraction ratio Input 1- metabolized= amount in blood Clearance Escaped F= absorption Volume of distribution Half life CLEARANCE A measure of the ability of the body to eliminate the drug Is the volume of plasma from which a drug is eliminated (metabolism and excretion) per unit time (L/h/70kg) CL (sys) = CL(kidney)+ CL(liver) + CL(other) CL = 0.693 * Vd/t1/2 Liver - biotransformation Renal - renal clearance Clearance: Constant (most drugs) Rate(elim) = CL * C Phenytoin must not follow normal process Drug concentration at which rate Capacity limited elimination - of elimination is 50% Vmax Ethanol aspirin Rate(elim) = Vmax * C / Km + C Can become Elimination low conc high Flow-dependent elimination (high extraction) Flow dependent (contrast) 1/2 life- time it takes for 1/2 drug to breakdown Fast as the drug comes in they are eliminated Introduction to pharmacokinics Dosing rate= rate of elimination MAINTENANCE/LOADING DOSES Dosing rate= clearance x target concentration Maintenance Dose = Dosing interval- every 12 hrs Dosing rate/F * Dosing Interval Maintenance dose= CL x TC/ F x dosing interval Loading Dose = Vd * TC a. Cl x tc= 2.8 L/h/ 70kg x 10 mg/L = 28 mg/ h/ 70kg b. Cl x tc/ F x dosing interval = 28 mg/h/70kg /0.96 x 12 hrs = 350 mg/ 70kg c. Vd x tc = 35L/70kg x 10mg/L = 350mg/ 70 kg Creatinine- kidney function Maintenance Dose = Dosing rate (cl x tc) /F * Dosing Interval (9 L/hr/ 70kg x 2 x 10^-6 mg/L (2 x 10^-9 1000ml= 1L —-> 10^-3)) / 0.7 x 24 = 6.17 x 10-4 mg/ 70kg  Factors affecting Bioavailability Introduction to pharmacokinics First pass hepatic metabolism Solubility of the drug Pharmacokinetics Chemical instability PK = investigates the movement of the drug through the body Nature of the drug formulation systems over time Bioequivalence - bet. two related drugs (compare F and Tmax) Four main pathways of drug movement and modification in the Therapeutic equivalence - compare efficacy (Cmax and Tmax) body include: and safety Absorption Distribution Urine Data Metabolism Cumulative urine data can be used to estimate bioavailability Elimination provided fe, remains constant. fe = ratio of the total amount excreted unchanged (Ae.) to the These four main pathways influences: dose given IV; ie Ae. Onset of drug action /Dose(IV). Therefore for an extravascular dose: Intensity of the drug effect fe = Ae. /F.Dose Duration of drug action Routes of Administration Route is determined by: The drug's properties (solubility, ionization) Therapeutic objectives (desirable features e.g rapid onset) Drug Distribution Enteral and Parenteral routes and effects on drug absorption Defined as the process by which a drug reversibly leaves the blood stream and enters the interstitium (extravascular fluid) Drug Absorption and /or cells of the tissues Absorption is transfer of drug from site of administration to the bloodstream Factors that Influence Drug Distribution Rate and efficiency of absorption depend on the route of Blood flow administration Capillary permeability - capillary structure and chemical nature Disease states and presence of food/water also affects absorption of the drug Physical factors also affect absorption- blood flow to absorption Binding of drugs to plasma proteins site, total surface area available for absorption, contact time at the absorption surface Volume of Distribution Hypothetical volume of fluid where the drug is dispersed Absorption Sometimes compare distribution of drug with the volume of Transport of a drug from the Gl tract occurs via various transport water compartments in the body mechanisms-e.g passive diffusion Three functionally distinct compartments drug once entered in Effect of pH on drug absorption- Henderson-Hasselbach equation body via whatever route: Plasma compartment Bioavailability Extracellular (interstitial) fluid Bioavailability (F) = fraction of drug that reaches the systemic Intracellular circulation Total body water (60%BW = 42L) F is determined by plotting the [Drug in plasmal versus time and Other sites measure the AUC AUC reflects extent of absorption of the drug AUC (oral) /AUC(IV) (* 100) = F oral Bioavailability Cont'd IV Dose: Plasma Compartment Dose(IV) = CL * AUC (IV) Drugs with large molecular weight or binds extensively to Extravascular Dose: plasma proteins, it is too large to leave the capillaries therefore F(e.v) * Dose(e.v) = CL * AUC(e.v) trapped in plasma compartment, which is about 6% of body Placing both formulae together yields, weight or 4L of body fluid in a 70kg individual. E.g Heparin Substitute CL: F(ev) * Dose(ev) = Dose(IV) / AUC(IV) * AUC(ev) Extracellular Fluid F(ev) = AUC(ev) / AUC(IV) * Dose(IV)/ Dose(ev) Drug with a low molecular weight but is hydrophilic can move through the slit junctions of the capillaries into the Relative Bioavailability interstitial fluid but hydrophilic drugs cannot pass the lipid This is when one compares the bioavailabilities of different dosage membrane of cells. E.g Aminoglycosides forms, different routes of administration, different conditions (fed/fast) Total Body Water Clearance assumes constant as with If drug has a low molecular weight but is hydrophobic, it can F(absolute) move into the interstitium through the slit junction and also it Amount absorbed = Total amount eliminated can move through the cell membranes into the intracellular F(A) * Dose(A) = CL * AUC(A) fluid. E.g ethanol F(B) * Dose(B) = CL * AUC(B) Introduction to pharmacokinics GIT Site Absorption Depends on: Other Sites Drug substance (API) properties E.g pregnancy, the fetus may also take up drugs and thus How drug product is formulated increase the volume of distribution Site of administration For absorption to be feasible the drug must be released from the Apparent Volume of Distribution formulation/product (except oral solutions), enter into the gut lumen's Volume into which drugs distribute is called apparent Vd fluids/juices, then dissolved free drug diffuse to the gut wall epithelia because drug does not stay in one compartment usually and also binds to cellular components such as proteins, nucleic Dissolution versus Drug Release acids and lipids Dissolution - refers to processes (including disintegration or capsule rupture) leading to the solvation of drug substance from orally Vd in Calculations administered IR solid drug products. Can extend to other oral dosage forms (oral prep) Vd can be used to calculate the amount of drug needed to Drug release - refers to the drug release of non-oral dosage forms (i.e. achieve a desired plasma concentration topical, transdermal, suppositories, liposomal delivery, etc.) test release E.g. If Conc'n of drug in plasma is Cl and the desired level of drug from patch which is higher is C2: , Vd * C1 = Amount of drug in plasma initially Processes Affecting Extent of Absorption During Gl Transit Vd * C2 = Amount of drug needed to achieve desired plasma Drug substance degradation conc'n Precipitation Vd(C2 - C1) = Additional dosage needed Motility Effect of Vd on Half life Gut wall metabolism A large Vd can result in an increase in half life First-pass metabolism Drug disposition (distribution and elimination) Binding of Drug to Plasma Proteins Binding capacity of albumin (reversible) - capacity and Drug Product Design Locally acting drug- drug product designed to deliver the drug directly to affinity the site of action before reaching the systemic circulation (limited systemic Competition for binding between drugs drug absorption) Drug displacement relationship to Vd Vd is large, These drugs are designed to penetrate mainly no further than the local tissue displacement from albumin to periphery is not Locally acting drug administered orally (local Gl effect) or applied topically significant as if Vd is small. If therapeutic index is small Drugs don’t always have to act within the blood then this can have consequences Mesalimine Look at the orange book Utilized help to generalized one equivalent to the next, definition learn Reminder 4 Rate of drug release and absorption is generally quantified by means of time BIOPHARMACEUTICAL to reach peak drug concentration (Tmax) and peak concentration CONSIDERATIONS IN DRUG (Сmах) The extent of drug release and absorption is represented by the Area under PRODUCT DESIGN AND IN VITRO the plasma concentration-time curve (AUC) Collectively, these parameters critical in determining the onset, intensity, and DRUG PRODUCT PERFORMANCE duration of drug action Reminder 1 Biopharmaceutics - the study of the physiochemical Biopharmaceutic Factors Affecting Drug Product Design properties of both the drug substance and the product as it Factors affecting BA (or Drug-System properties): relates to the bioavailability of the drug Drug substance properties Formulation of the drug product Biological characteristics of the patient Goal is to ensure consistent drug product quality and Excipients: included in the dosage form but are inert with respect to desired patient-centric therapeutic effect pharmacodynamic activity Excipients — important in manufacture and functionality (w.r.t. drug Reminder 2 release/dissolution) of drug product Definition of Bioavailability - refers to the rate and extent Drug disposition influenced by specific formulation of the drug of appearance of active drug at the site of action, which is Example, encapsulated drug in liposomes/microspheres may change the measured as a fraction (percentage) of drug that reaches the drug distribution and systemic clearance; addition of mannitol may change systemic circulation (Cmax RELATES TO Tmax and AUC) the renal clearance Reminder 3 Considerations in the Design of a Drug Routes of administration for drug products - oral, rectal, Product Physiochemical properties of the drug substance nasal, ocular, pulmonary, transdermal, aginal, otic, Route of drug administration parenteral (e.g.IV, intra-arterial, intramuscular, Desired PD effect intrathecal, subcutaneous) Toxicologic properties of the drug substance and excipients Choice of route depends on several factors Effect of excipients and dosage form Passive route of a drug can be via paracellular or Manufacturing processes (site of manu and process) transcellular mechanism depending on hydrophilicity and size of the drug molecules ( influence bioavailability )  BIOPHARMACEUTICAL CONSIDERATIONS IN DRUG PRODUCT DESIGN AND IN VITRO DRUG PRODUCT PERFORMANCE Route of Administration Noyes-Whitney Equation Anatomy and physiology of the administration site Noyes and Whitney (1897)- benzoic acid and lead Ingredients to be used chloride in distilled water Eye: Propose that saturated solution film Cs allows for pH- buffer system- ph of eye tear fluid diffusion to take place Isotonicity Rate of dissolution is proportional to the difference Minimize irritation between the saturation solubility and the instantaneous Combination drug/device product bulk (well-stirred) concentration Biopharmaceutic Considerations Dissolution and Noyes-Whitney Eqn. These determine the dose and dosage form of a product mg, mcg,g The Noyes-Whitney equation shows dissolution Strengths of a dosage form usually expressed in unit influenced by: Dose adjusted based on weight or surface area Physiochemical characteristics of the drug The solvent the drug is dissolving in Rate Limiting Steps in Drug Absorption Know this Level of agitation in the bulk fluid medium Delivery of drug product formulation Temperature of the fluid medium (solvent) stimulate body Release of the drug substance from the formulation temp) Transportation to absorption site (cellular permeation) For non-locally acting drugs, post absorption, rate dependent steps Factors Affecting Drug Dissolution (Solid Oral ER formulation, the release of the drug from the formulation is the Dosgage Form) rate limiting step The physical and chemical nature of the active drug For solid oral IR tablets, disintegration (rate limiting step)- substance deaggregate then dissolution The nature of the excipients The method of manufacture Disintegration The dissolution test conditions Disintegration - process dosage form progressively transforms to smaller drug particles 500-900mls paddle or basket- spin Chewable tablets, troches, liquid filled soft gelatin capsules, SR drug Conc in ficks law- plasma products (osmotic pump, etc. oral dosage forms) Disintegrants include Na starch glycolate, crospovidone, microcrystalline cellulose)- faster- combination Mechanisms involved include wicking and swelling High compression or insufficient disintegrants - poor disintegration Wicking and Swelling Noyes- Whitney vs ficks law Define signs and what is similar and difference Mechanisms List 5 types of transportation and describe 2 of them (Para, trans, passive diffusion, simple diffusion, carrier mediated- active and facilitated) api solubility, partition coefficient, ionization, Disintegration in Lieu of Dissolution product (dosage form- controlled released extended) 1. The product under consideration is rapidly dissolving Site of administration- more blood vessels- greater 2. The drug product contains drugs that are highly soluble absorption, fatty area- unionized drug pass through throughout the physiological range Secretion- cell to lumen 3. A relationship to dissolution has been established or when Define and distinguish drug release and dissolution disintegration is shown to be more discriminating than Define disposition dissolution Time reaches mec - onset In vitro dissolution cannot be practically characterized for highly Intensity, duration soluble compounds List 5 factors needed for drug product design and why Dissolution Define disintegration and describe diagram- The process by which a solid drug substance becomes dissolved in a wicking and swelling solvent over time (dynamic) Solubility is the mass of solute that dissolves in a specific mass or volume of solvent at a given temperature (equilibrium) In-vivo dissolution can be rate limiting step (poor aqueous solubility) In-vivo dissolution mapped to in-vitro dissolution - quantitatively predict BA (in-vitro-in-vivo correlation)  BIOPHARMACEUTICAL CONSIDERATIONS IN DRUG PRODUCT DESIGN AND IN VITRO DRUG PRODUCT PERFORMANCE Physiochemical Properties of the Drug Solubility, pH and Drug Absorption Cont'd Effect on dissolution kinetics - Solubility improves with a basic or acidic excipients) Important in design of a drug product Salt formation of the drug may change the drug's physiochemical properties including solubility, chemical The ability of a drug to exists in various crystal forms stability, polymorphism, manufacturability, etc. (polymorphism) Potential for converting from the salt form to the unionized Moisture absorption may affect the physical structure drug form must be considered for optimal product design as well as stability of the product The partition coefficient may give indication of the The stability-pH profile is a plot of the reaction rate constant relative affinity of the drug for oil and water. for drug degradation versus time. (Reaction w excipients) absorption If drug decomposition occurs by acid or base catalysts then The compatibility of the excipients with the drug and prediction of degradation of the drug in GIT can be made sometimes trace elements in excipients may affect the For example, erythromycin has a pH-dependent stability of the product.- affect stability stability profile. The stability of solutions is often affected by the pH of the vehicle; furthermore, because the pH in the Purpose of Dissolution and Drug stomach and gut is different (Henderson- hasselbach) Release Tests The presence of impurities may depend upon the Aid for formulation development and selection synthetic route for the active drug and subsequent Confirmation of batch to batch reproducibility purification. Demonstrate that the product performs consistently The presence of chirality may show that the isomers throughout its use period of shelf life have differences in PD activity (response/ effect) Establish IVIVC/IVIVR in Vito in vitro correlation The evaluate the biopharmaceutic implications of a minor / Other considerations include: moderate product change (FDA Guidance, 1995) IV solutions which are difficult to prepare with drugs that have poor aqueous solubility Biopharmaceutics Classification Drugs that are physically or chemically unstable System requiring special excipients, coatings, or Class 1: High solubility-high permeability manutacturing processes to protect the drug from Class 2: Low solubility- high permeability degradation Class 3: High solubility-low permeability Drugs with potent PD response, (antineoplastics) Class 4: Low solubility-low permeability such as estrogens and other hormones, penicillin Classification based on Fick's first law antibiotics, cancer chemotherapeutic agents, and others, can cause adverse reactions to personnel who Solubility Rules (USP) are exposed to these drugs during manufacture Physiochemical Properties for Consideration in Drug Product Design Absorption, ionization Dissolution rate of product Particle Size and Drug Absorption Dissolution kinetics is affected by particle size Noyes-Whitney equation: surface area of the drug is Storage proportional to the dissolution rate Surface area increased by reduction in the particle size Outcome/ response Geometric shape also affects the surface area Surface area constantly changes during dissolution Particle physiochemical properties (hygroscopicity, morphology and Solubility, pH and Drug Absorption size) important for drug substances with low water solubility The solubility-pH is a plot of the solubility of the drug (BCS Class II); rate limiting step for absorption at various physiologic pH values Drugs with low aqueous solubility (griseofulvin, Must consider natural pH of the environment of the nitrofurantoin, many steroids) stomach or small intestines Reduction of particles by milling to a micronized form Solubility-pH profile gives a first impression of the improves oral absorption- griseofulvin challenges to achieve complete dissolution for a dose Disintegrants - rapid disintegration and drug release of a drug in the stomach or in the small intestines Surface-active agents - increase wetting and solubility Nano-sizing - producing even smaller drug substance particles  BIOPHARMACEUTICAL CONSIDERATIONS IN DRUG PRODUCT DESIGN AND IN VITRO DRUG PRODUCT PERFORMANCE Polymorphism, Solvates and Drug Absorption Influence of Excipients on Drug Polymorphism - refers to the arrangement of a drug substance in various crystal forms or polymorphs Product Performance Amorphous forms- noncrystalline forms Excipients - are included in the formulation to provide Solvates - are forms that contain a solvent (solvate) or certain functional properties to the drug and dosage water (hydrate) form Desolvated solvates - are forms that are made by Functional properties of the excipients: removing the solvents from the solvate Improve manufacturability of the dosage form Anhydrous state - drugs existing with no water of Stabilize the drug against degradation hydration Decrease gastric irritation Drug products manufactured with polymorphs have Control the rate of drug absorption from the absorption the same chemical structure but different physical site properties (different solubility, hygroscopicity, Increase drug BA, etc density, hardness, compression characteristics) Lubricant, magnesium stearate, may repel water and Some polymorphic crystals have lower aqueous reduce dissolution when used in large quantities solubility than the amorphos form causing insolubility Coatings, particularly shellac, will cross link upon aging Chloramphenicol has several crystal forms The B- and decrease the dissolution rate form or polymorph is more soluble and better Suspending agents that increase the viscosity of the absorbed drug vehicle, thereby diminishing the rate of drug The crystal form that has the lowest free energy is the dissolution most stable polymorph Low concentrations of surfactants decrease the surface A drug existing in the amorphous form generally tension and increase the rate of drug dissolution dissolves more rapidly than the same drug in a crystalline form Common Excipients Used in Solid Drug Products Some polymorphs are metastable and may convert to a more stable form over time Change in the crystal structure of the drug may cause cracking in a tablet or prevent granulation from being compressed into a tablet Dissolution Behavior of Erythromycin Hydrates and Anhydrous Form More water, dissolves faster Common Excipients Used in Oral Liquid Drug Products Mean Blood Serum Levels of Chloramphenicol Palmitate Suspensions Containing Varying Effect of Excipients on the Pharmacokinetic Ratios of a - and B-Polymorphs Parameters of Oral Drug Products Changing B form, higher, more soluble BIOPHARMACEUTICAL CONSIDERATIONS IN DRUG PRODUCT DESIGN AND IN VITRO DRUG PRODUCT PERFORMANCE Effect of Lubricant (Magnesium Stearate on Drug Dissolution) Lesser, faster Not much, tab won’t dissolve Effect of Lubricant (Magnesium Stearate on Drug Absorption) List physiocochemical properties and describe  Considerions in the Design and Performance of Drug Products Definition of Drug Product Considerations Biopharmaceutics Bioavailability of the Drug: Manufacturing factors and physiochemical properties Pharmacological response related to drug concentration at site of influencing rate and extent of drug absorption from site of action - BA of a drug (dosage form) - drug product efficacy administration Factors affecting how much of the drug absorbed at site: physiochemical properties, etc Biopharmaceutic Considerations Stability of the drug in the GIT Pharmacodynamics Poor BA (first pass effect (presystemic elimination) Drug substance Oral route (drug not absorbed or high dose is toxic) use Drug product alternative route of administration Patient › Manufacturing Drugs That Undergo Significant Liver Metabolism Role of Biopharmaceutics * Link between in vivo product performance (BA, onset of action, safety, efficacy) to the drug product's manufacturing and physiochemical properties. In vitro-in vivo correlation Establishes a relationship between a biological property of the drug (e.g.PD effect or plasma conc'n) and a physiochemical property of the drug product containing the drug substance (e.g. dissolution) Dose Considerations Dose alteration required because of differences in PK parameters Pharmacodynamic Considerations - metabolism, renal clearance, weight, Vd, age, disease stage Effect of drug in the body and its mechanism of action - (individualized dosing) therapeutic response, ADRs Also dose titration Example nitroglycerin - highly metabolized if swallowed Above reasons for various dosing strengths Scored tablets Nitroglycerine Dosage Forms and Route of Administration Dose = drug + excipients (size) Size and shape of solid oral drug products - ease in swallowing (caplets vs round, large tabs) Large amount of fluids helps swallowing difficulties Dosing Frequency Considerations Therapeutic dosage regimen - dose, dosing freq - total daily dose Dose = amount taken at one time (mass, volume, number (puffs/ drops)) Dosage regimen = freq at which drug doses are given Drug Substance Considerations Total daily dose = dose and freq Five stages of drug development: Dosing freq determined by drug clearance and target plasma Disease target identification concentration Target validation- protein, gene Short half life or rapid clearance from the body, the drug must be High-throughput identification of drug leads given more frequently or administered as an ER drug product Lead optimization Preclinical and clinical evaluation Patient Considerations Stages 3-5 involves characterization of the PK properties Drug product and therapeutic regimen must be acceptable to (ADME) patient Poor patient compliance - result of poor product attributes (bitter Drug Substance Considerations Cont'd taste, swallowing problems, SEs, odor, etc) In silico drug design: drugs designed/ discovered based on Benefits: special packaging, ODT oral disintegrating tablet and computational methods (mathematical modelling - molecular chewables structure) Transmucosal (nasal) administration of antiepileptic drugs (more PK/PD modelling and simulation - quantitative assessment of convenient, easier to use, safe) vs rectal administration dose/exposure-response relationships with application to early/ Packaging late stage of drug development Genetic polymorphisms of CYP2D6 and CYP2C19 enzymes - Design and Performance of Drug Products extensive metabolizers and poor metabolizers Route of administration affects the rate and extent (BA) of the Pharmacogenomics application into drug development and drug; hence, can alter/modify onset, duration, intensity of clinical trial evaluation the pharmacological response (efficacy and safety) Increase efficacy and reduce toxicity/SEs Compliance- follow Emergency routes - rectal, nasal, buccal mucosa Adherence- patient themselves to take initiative to fit in schedule Dosage and Kinetics of Nitroglycerin in Various Dosage Orange Book Forms Discuss the Orange Book - Use Interpretation of data Terms and abbreviations mentioned etc Methods for Assessing BA and BE In vivo measurement of active moiety or moieties in biological fluid (PK study) In vivo pharmacodynamic (PD) comparison BIOEQUI VALENCE In vivo limited clinical comparison In vitro comparison Objectives Any approach deemed acceptable (FDA) At the end of this lesson you should be able to: Explain the definitions related to drug development, performance and equivalence Questions: Discuss Orange Book State drugs that undergo significant liver metabolism Describe the therapeutic equivalence evaluation codes Methods for assessing BA and BE Define the Terms API Abbreviated New Drug Application (ANDA) Interaction Bioavailability Physiochemical properties basic/acid Bioequivalence requirement Target local/systemic Bioequivalent drug products Solubility Biosimilar/ biosimilarity Partition coefficient Brand name Ph Chemical name PKa Drug product Patient demographics age, size, gender Drug product performance Route Drug substance Excipients Equivalence Drug environment basic or acidic Generic name Storage and Transport Multisource drug products Packaging Generic substitution Nature of formulation Reference listed drugs Pathological conditions Pharmaceutical alternatives Genetics Pharmaceutical equivalents Dose, frequency etc considerations Pharmaceutical substitution Therapeutic alternatives Therapeutic equivalents Therapeutic substitution Relative bioavailability Absolute bioavailability