Exam 3 Flashcards

Question

Organoleptic Senses to consider when coating/binding (clinical trials) treatments

Answer 1

- sight (size, color, shape, markings) - smell - sound (tablet/pellet inside a capsule) - taste - touch

Answer 2

- disintegrants-enhance rate of disintegration/dissolution - coatings-control release - flavors/sweeteners-mark drug taste - colors-recognition - miscellaneous ingredients

Answer 3

- absorbing surface area - residence time at absorption site - pH changes in lumen - permeability/perfusion (functional and molecular characteristics of transporter and metabolism) - dietary fluctuations/effects - complexation/protein binding - biliary uptake and clearance

Answer 4

- predominantly used for external surfaces although endothelial cells are epitheliod (sit on a layer of extracellular matrix proteins; epithelial cells are polarized with directional transport) - there are several different types - endothelial cells line the inside surfaces of body cavities, blood vessels and lymph - they have simple squamous morphology. Endo = in, therefpre internal surfaces

Answer 5

- thin layer of flattened cells that are relatively permeable - lines most blood vessels - placenta, endothelial cells (?)

Answer 6

usually found in the GI tract

Answer 7

comprised of several layers with different shapes - usually required to stretch

Answer 8

multiple layers of squamous cells that cover areas subject to wear and tear - skin is one type that the barrier function comes from keratinization

Answer 9

- all living cells are enclosed by one or more membranes, which define the cell as the living unit - the membrane isolates the cellular contents from the environment - forms a barrier - the cell membrane is a semi-permeable membrane, permitting the rapid passage of some chemicals while retarding or preventing the passage of others - cellular lipid composition is polarized and intracellular membrane lipids are different than extracellular lipids

Answer 10

No, it provides fluidity at lower levels. Actually, when it exceeds a certain level in a membrane, the membrane undergoes a phase transition and forms a liquid crystalline state. We call this hardening atherosclerosis when it occurs in the vasculature.

Answer 11

- important for the function of the confluent epi-/endothelia - restrict solute movement between the cells (paracellular) - polarize cells into apical (luminal - blood facing) and basolateral (abluminal - brain facing) areas - allow for differing functions between the two membranes - TJs can involve up to 50 proteins

Answer 12

Look up equations.

Answer 13

- Passive (non-saturable) * **paracellular (between cells) * **Transcellular (through cells) - Carrier-Mediated (saturable) * **active (energy dependent) * **facilitated diffusion (energy independent)

Answer 14

See chart.

Answer 15

Drug transporters are membrane-bound proteins widely distributed throughout the body, prominently on apical and basolateral surfaces of organs involved in clearance Physiological role of these transporters is to move important molecules across membranes; this capacity includes moving drug molecules across membranes Drug transporters are a crucial determinant of tissue and cellular distribution of drugs, not only for drug clearance but also sanctuary organs Variations in drug transporter activity can be major determinants of drug response and drug safety This has primarily been identified in adults with much less data in children

Answer 16

43 Subfamilies > 300 members identified Generally influx or secretory efflux transporters PepT1, OATs, OATPs

Answer 17

7 Subfamilies 50 members presently identified Generally efflux- multidrug resistant transporters P-glycoprotein, MRPs

Answer 18

Refer to diagram.

Answer 19

Transfer substrates into cells

Answer 20

pump substrates out of cells

Answer 21

Transfers substrates into the systemic blood circulation

Answer 22

transfer their substrates from the blood circulation into bile, urine, and/or GI lumen

Answer 23

Hydrophilicity. Molecular Size and Shape pKa of the ionizable groups Linear increase in permeability with increasing concentration Adjuvants can open tight junctions and increase transport

Answer 24

Affinity (Km), Capacity (Vmax/Jmax) Concentration dependent saturation Expression level (constitutive, induced). Function (drug-drug & drug-nutrient interactions, competitive inhibition.) Excipients like surfactants can limit the effects of efflux by Pgp or BCRP.

Answer 25

The FDA is now paying significant attention to cell based permeability assay variation. Affinity for multiple transporters can obfuscate physiologically relevant predictions Inherent variability leads to differences in PAPP values for the same drug Divided into three categories Cell Culture Methods/Techniques Transport Experiments Data Analysis

Answer 26

Oral Cavity-Buccal (stratified squamous epithelium) and Sublingual (simple squamous epithelium) Esophagus is comprised of a stratified squamous epithelium, with the trachea being comprised of psuedostratified squamous epithelial cells. Stomach is comprised of predominantly columnar epithelial cells, mixed with other cell types like mucus producing goblet cells, and parietal (acid secreting) and enterochromaffin-like (histamine secreting) cells. The Small and Large Intestines are also lined with predominantly columnar epithelial cells. These cells are mixed with many different cell types. Rectum has an upper (simple columnar) and lower (stratified squamous non-keratinized region transitioning to stratified squamous keratinized region near the anal sphincter) half.

Answer 27

To digest food and control the flow of its contents into the intestine. * Acts as a food reservoir * Processes food into fluid chyme for nutrient absorption * Regulates food delivery to intestine * pH protects against most bacteria, allows pepsin to function Fasted pH in normal, healthy adults < 3 Fed pH is in the range of 5 to 7. Gastric emptying half-time is about 30 min. Fasted emptying cycles through 4 phases culminating with a “Housekeeper” Wave. Fed state, no defined cycle.

Answer 28

Three primary regions: 1. Fundus- contains gas and produces contractions to move stomach contents 2. Body-reservoir for ingested food and fluids 3. Antrum-lowest part of the stomach, funnel shaped, contains the pyloric region and controls flow into the small intestine.

Answer 29

Mouth to Anus transit time = 24-32 hours. Small Intestinal Transit Time = 3 hours. Most absorption occurs in the Small Intestine Small Intestinal pH = 5.0 to 6.5 Colon drug absorption mainly occurs in the ascending region nearest to the SI

Answer 30

Characteristics: - Most transporters are located in SI. - Upper SI = mixing. - Lower SI = electrolyte. - Colon = fluid and electrolyte absorption.

Answer 31

Microvilli increases surface area in the small intestine by 600x

Answer 32

See figure.

Answer 33

Columnar eptihelial cells form a single continuous layer of absorptive cells ( 25µm high and 8µm wide) covering each villus. Separated from lamina propria (blood vessels and lymph) by basal lamina-300Å thick-comprised of glycoproteins and penetrable by lymphocytes (8-12µm).

Answer 34

-3x more crypt then villi, comprised of undifferentiated cells that prolierate -Goblet cells-mucus secreting; Paneth cells-regulate microflora; and Argentaffin cells that secrete mucus component.

Answer 35

-Absorptive enterocytes -A few goblet cells do appear, as well as M-cells which overlay the Peyer’s patch or lymphoidal tissue -Cells from the crypt migrate to the villus tip and are extruded-sloughed off at the tip-enterocyte lifetime 2-3 days, entire lining of the GI tract turns over every 2-4 days.

Answer 36

125 cm long from caecum to anus, with transport being much slower then in small intestine. - Ascending colon 20 cm long - Traverse colon 45 cm long - Descending colon 30 cm long-rest is sigmoid Varies in thickness from 2.5 cm in the sigmoid region to 8.5 cm in the caecum Ileocaecal valve limits food flow from the ileum into the caecum and vice-versa. Colon is responsible for water and electrolyte absorption (caecum, ascending colon)-prevents dehydration and leads to formation of solid fecal matter.

Answer 37

Colon structure - Serosa-squamous epithelium covered with adipose tissue - Muscularis Externa-inner circular muscle layer and incomplete outer longitudinal layer - Submucosa and mucosa Colonic Mucosa-three layers - Muscularis mucosae - Lamina propria - Epithelium Proximal colon is usually where enteric coated formulations target by oral administration. Distal colon-rectal administration, e.g. suppositories.

Answer 38

Rectum has an upper (simple columnar) and lower (stratified squamous non-keratinized region transitioning to stratified squamous keratinized region near the anal sphincter) half. Highly folded The stratified squamous, non-keratinized epithelium, in particular, allows high drug absorption. There are a number of high potency drugs that may be delivered rectally. Many young and old patients have gag reflex problems with pills, extemporaneous compounding of the drug in suppositories is used. Low residence time

Answer 39

Transporters and enzymes vary along the GI tract. Variability is enormous in GI fluid composition Diet and chemical exposure varies Pharmacogenetics and genomics are huge issues Interindividual variation is also significant (intra?) Drug-nutrient and drug-drug interactions are common. So much more…Shout out to the gut microbiome Bottomline: One Size formulations do not fit all.

Answer 40

``` Factors influencing drug solubility: -Buffer capacity -Bile salts -Regional fluids -Other drugs -Potential issues from endogenous substrates ```

Answer 41

Critical Points: - Disposition is comprised of distribution and Elimination - Elimination describes the removal of the drug from the body and includes both: * **Metabolism * **Excretion - Toxicity is a result of exposure - There can all be defined by the plasma vs. time curves, which is the focus of our lectures.

Answer 42

*Described by concentration time profiles – shape of the profiles depends on point of observation *Compartments represent kinetically similar tissues or spaces *Processes can be reversible or irreversible *Processes can be linear or nonlinear *Fast and slow processes tend to “disappear”

Answer 43

- Bioavailability refers to the rate and extent of drug absorption - Absolute bioavailability is the AUC of a given dosage form compared with the AUC of the same dose injected intravenously. - Relative bioavailability refers to the AUC of a given dosage form compared to an arbitrary reference standard - Bioequivalent does not mean that the therapeutic effect of two dosage forms are equivalent.

Answer 44

-Dose covers two aspects: ***The amount of chemical in which the whole organism is treated. ***The local concentration of the chemical at the biological response site. -The relationship between dose and receptor concentration is a function of the ADME.

Answer 45

- Coatings can be applied to control diffusion rates and modify the release properties of the drug from the interior. - Disintegrants can be used to control regions of release based on physicochemical properties - Lubricants can slow dissolution based on properties - Internal excipients can be used to modify the release rates as well * **Swellable matrices * **Non-swelling matrices * **inert plastics.

Answer 46

- Coatings are applied to the outside of solid dosage forms to accomplish the following: * **protection of agent from air and/or humidity * **mask taste * **provide special drug release * **aesthetics * **prevent inadvertent contact with drug (i.e.: proscar and pregnant women) - Aqueous film coatings generally contain * **film-forming polymer * **plasticizer to produce flexibility and elasticity of coating * **colorant and opafier * **vehicle

Answer 47

- film-forming polymer-produce smooth films - alloying substance to provide water solubility or permeability to the film - plasticizer to produce flexibility and elasticity of coating - surfactants enhance film coat spreading - colorant and opafier improve appearance - sweeteners, flavors, and/or aromas - glossant providing luster - volatile solvent allows spreading & evaporation

Answer 48

Added to dosage forms to prevent the early release of an API in a region where it may undergo chemical or metabolic breakdown.

Answer 49

1. To prevent acid sensitive APIs from gastric fluids 2. To prevent gastric distress from the API 3. To target API delivery to a site in the intestine 4. To provide a delayed/sustained release. 5. To deliver the API in a higher local concentration in the intestines where it may be absorbed and have a higher bioavailability.

Answer 50

describes a pharmaceutical dosage form formulated to slow the release of a therapeutic agent such that its appearance in the systemic circulation is delayed and/or prolonged and its plasma profile is sustained in duration. In other words: the onset of pharmacologic action is delayed, but its therapeutic effect has a sustained duration.

Answer 51

goes beyond sustained release and implies a reproducibility and predictability in the drug release kinetics. Therefore the kinetics from one dosage unit is reproducible and predictable from one unit to another. Allows us to maintain a narrow drug plasma concentration-Steady State

Answer 52

-Coated Beads, Granules, or ---Microspheres ***Coating on the beads controls release by programmed erosion Example: Contact - Multitablet system. * **Small tablets placed in a gelatin capsule - Microencapsulated * **Solids, liquids, or gases are encapsulated into walled material, which allows spreading of microparticles across absorbing surface. - Drug Embedding in a Slowly eroding or Hydrophilic matrix * **Drug is homogeneously dispersed in the eroding matrix and its release is controlled by erosion rate.

Answer 53

At steady state, the rate going into the body must equal the disposition (the rate distributing early and being metabolized, and/or being excreted from the body throughout).

Answer 54

- Exhibit neither slow or fast rates of absorption and excretion - Uniformly absorbed from the gastrointestinal tract - Administered in relatively small doses - Have good safety/therapeutic window - Chronic therapies better suited than acute

Answer 55

- Drug molecules at the surface dissolve to form a saturated solution. - Dissolved drug molecules pass throughout the dissolving fluid (diffuse) from the area of high concentration to low concentration - Drug molecules diffuse through the bulk solution to the absorbing mucosa and are absorbed - Replenishment of drug molecules in the diffusion layer is achieved by further dissolution

Answer 56

- Surface Area Increases when solids are broken up into smaller pieces - Red Surfaces are new surfaces without effecting volume - Effect continues as you move from tablet to granules to particles - Increased surface area leads to increased dissolution rate

Answer 57

-3 factors can limit the ability of a drug to absorb after oral administration *Solubility +++Can’t Get Enough Drug Into Solution *Dissolution +++Can’t Get Drug Out Of Tablet *Permeability +++Can’t Get Drug Across GI cell membrane

Answer 58

- Drugs with very poor solubility are often limited as druggable candidates - Represented as a small Cd value in previous equations - Dosage form dissolves fast and drug permeates readily - Increasing dose doesn’t increase blood levels as the GI fluids are already saturated

Answer 59

- Drug is unable to dissolve into the solution from the dosage form in sub-saturated fluid - Dissolution Time is greater than the time for absorption in the intestines - Often due to poor formulation/manufacturing - Need to have a tablet that can dissolve but also stand up to shipping and handling

Answer 60

- Characteristic of the API itself similar to Solubility Limited - Dissolution is fast with sub-saturated fluids - Increasing the amount of drug increases absorption - See Notes up to now and previous slide with Permeability equation * **Increasing Cd by increasing the amount of drug * **Increases dM/dt which is absorption in this case

Answer 61

- physicochemical properties-drug | - physiological properties-membrane

Answer 62

- physicochemical properties-drug | - physicochemical properties-formulation

Answer 63

A drug product that is comparable to a brand/ reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use.

Answer 64

- Therapeutic Equivalence * **Pharmaceutical Equivalence * **Bioequivalence -A generic product judged therapeutically equivalent to the reference listed drug will have the same identity, strength, quality, safety, and efficacy.

Answer 65

-Same active ingredient(s); same dosage form; same route of administration; identical in strength or concentration; and may differ in characteristics such as shape, excipients, color...

Answer 66

-Pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered to humans at the same molar dose under similar experimental conditions - In vivo measurement of active moiety(ies) in biologic fluids, or * **In vivo pharmacodynamic comparison * **In vivo limited clinical comparison * **In vitro comparison

Answer 67

-2885 patients receiving phenytoin, carbamazepine or valproic acid were queried. - Patient Reporting Results: * **70.5% no problems after switch * **10.8% range of problems including reappearance of seizures * **9.9% unspecified issues * **8.8% other issues, but no follow-up included -30% of respondents reported an issue with a switch to a generic drug product.

Answer 68

- Drug molecules at the surface dissolve to form a saturated solution. - Dissolved drug molecules pass throughout the dissolving fluid (diffuse) from the area of high concentration to low concentration - Drug molecules diffuse through the bulk solution to the absorbing mucosa and are absorbed - Replenishment of drug molecules in the diffusion layer is achieved by further dissolution

Answer 69

- A drug product is considered bioequivalent if the 90% confidence interval of the ratios of the test to reference log-transformed mean values for AUC and Cmax are within 80%-125%. [both Cmax (111% - 126%) and AUC (97% - 108%) from the Meyer study]. - Differences in Cmax and Tmax were due to faster dissolution of the generic products comparative to the RLD.

Answer 70

-Even though all four products demonstrate a linear relationship between the percent dissolved and the percent absorbed, no single correlation could be established to predict the bioavailability of all four products no correlation was possible between dissolution rate and AUC ***More Importantly, there is definitely an issue in the interchangeability of these products.

Answer 71

- Dosage form design requires consideration of patient related variables - Patient related variables are not accurately assessed during development and scale up. - “Absorption windows” are defined more based on physical chemical properties and not physiology. - Better in vitro and in vivo testing models are required for optimizing dosage form design and scale-up.

Answer 72

- Drug performance (PK/PD) is controlled by the interplay of excipients (formulation), the physicochemical properties of the drug, and the physiological barriers between the GI tract and the site of action. - Oral formulations can control the absorption rate (Kabs), which then has to be optimized with respect to disposition to yield a safe and efficacious response. - Dosage form design is dynamic and is unpredictable, so patient habits have to be considered for dosing regimens. - Patients will vary in response, so this needs to be considered. - Generic formulations are not the innovator, and thus can cause some problems with performance

Answer 73

~60 million women at reproductive age ~10% of these women become pregnant annually ***Many are on meds for treating pre-existing conditions (e.g., epilepsy, hypertension, depression, asthma, etc.) ~But…PK of drugs in pregnancy is complex * **Physiological changes alter ADME of drugs * **Toxicity is a significant concern

Answer 74

- The developing fetus undergoes rapid changes during the 9 month gestation period - Genetics, diet, environment, etc. can all impact the fetus. - Fetal imprinting has been linked to: * **Cardiovascular disease-Barker Hypothesis * **Neurological disorders * **Obesity/diabetes, as well as others - Very difficult to predict human effects based on: * **Many factors involved aside from genetics, e.g., diet * **Many exposure studies done in animals.

Answer 75

- Historical cases with drugs like thalidomide in the 1950’s induced in utero malformations. - Exposure to xenobiotics are poorly understood. For example, endocrine disrupting chemicals (EDC; e.g., diethylstilbesterol) led to in utero programing of cancer in adolescence. - Animal models have differing sensitivity to xenobiotic exposure than humans - Human data is sparse, but xenobiotic exposure can lead to changes in developmental PK/PD. - The target moves even further due to the environment!

Answer 76

- “The joint goal for industry, regulators, practitioners and patients is to encourage pediatric drug development in order to create a situation where substantially more children have access to safe and effective medication…” - Early USA regulation- 1962 Kefauver-Harris Drug Amendments required efficacy and safety demonstration for FDA approval and marketing. - Legislative incentives/mandates in place to promote pediatric development * **FDA: Pediatric Plan, BPCA, PREA * **EU: Pediatric Investigation Plan (PIP) * **WHO: Make Medicines Child Size

Answer 77

-Testing drugs in children presents considerable scientific, clinical, ethical, technical, and logistical challenges. - Several practical challenges have discouraged the testing of drugs in pediatric populations including the lack of: * **Incentives for companies to study drugs in neonates, infants, and children * **Technology to monitor patients and assay very small amounts of blood * **Suitable pediatric clinical infrastructure for drug trials. - Is 6 months of exclusivity worth the risk? - After 6 months, is it cost effective to drop pediatric programs?

Answer 78

- Children are “therapeutic orphans” - Only 20-30% of approved drugs have pediatric labeling - FDA has encouraged pediatric studies * **Financial incentive to conduct studies - -----Orphan and off-patent drugs - no incentive to do studies * **Increased studies resulted in new labeling for 40 drugs. * **For approval of selective number of new drugs pediatric studies have been required. - Resources * **Center for Drug Evaluation and Research at FDA - www.fda.gov/cder/pediatric/ * **Pediatric Drug Labeling: Improving the Safety and Efficacy of Pediatric Therapies.

Answer 79

- Descriptive pharmacology (especially for new drugs) in pediatric patients is often lacking * **Children are not “miniature adults” - -----Dosing based on scaling (by body weight or body surface area) not always predictable for a given drug. * **Animal studies not always predictive. * **Clinical studies in children fraught with ethical and financial hurdles. * **Administration of drug can also be problematic.

Answer 80

- 1883 Patients treated with high dose MTX in a Children’s Oncology Group (COG). - GWAS with over 5 million SNPS and MTX clearance was performed. - Multiple dosing was performed. - MTX clearance differences were associated with SLCO1B1 SNPs, which are the most important genetic variations out of 1279 of the patients ***Low clearance rates are associated with higher toxicity. Dose lowering adjustments and higher hydration rates should be required in children carrying these phenotypes.

Answer 81

- The relevance of animal models (differences in the developmental timing of anatomical, physiological, biochemical and physicochemical events) can limit extrapolation to humans * **Length of gestation and timing of events * **Relative organ function maturity at birth -Significant species differences exist in some transport proteins and regulatory machinery

Answer 82

- Biological Challenges * **Ontogenic Changes * **Compositional Changes - Clinical Challenges * **Clinical Trials * **Caregiver Requirements - Formulation Challenges * **Dosage Form Selection * **Flexibility in Dosing * **Excipient Selection * **Taste Masking

Answer 83

-Paradigm shift for industry (know this): ***Traditional views over the last couple of decades have been to protect children from clinical research. ***(However, the current regulatory paradigm shift is to now protect children through clinical research. - New chalenges based on the Paradigm shift * **Children are not minature adults * **Pediatric patients need to be age classified * **Pediatric patients require age appropriate formulations that used to be primarily made through compounding * **First in child safety and efficacy preclinical models are lacking

Answer 84

- The Safety and Toxicology of Excipients for Pediatrics Database * **Collaboration between EMA and NICHD * **Draws considerable attention to use of traditional excipients, particularly co-solvents for pediatrics vs. adults * **Encouraging greater use of solid dosage forms

Answer 85

- Ability to incorporate BCS Class I and III * **Less effect of formulation * **Likely more beneficial for testing of medications already on the market - Easy translation to market formulation * **Pediatric compliance * **Flexible dosing * **Protected from degradation of vehicle or stomach - Minimal excipients * **Single filler, disintegrant, lubricant with functional coatings - Same or similar manufacturing conditions * **Size is constant, number can fluctuate - Fractional factorial DOE approach * **Many process and formulation variables

Answer 86

Advantages - Acceptable for patients with dysphagia - Ease and accuracy of dosing - Increased stability compared to solutions/suspensions - Faster onset of action - Life cycle management Disadvantages - Difficult to manufacture - Moisture sensitive - Limited dosing capacity - Increased packaging costs

Answer 87

-Age based dosage form selection - Need for descriptive pharmacology (especially for new drugs) in pediatric patients * **Children are not “miniature adults” - -----Dosing based on scaling needs to better incorporate age based ontogenic changes. * **Animal models need to be refined for prediction. * **Enable clinical studies in children by tackling some of the ethical and financial hurdles. * **Better means of drug administration are needed.