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PHRM 828 exam 2 > exam 2 > Flashcards

exam 2 Flashcards

1
Q

excipients- the key ingredients(s) for controlling drug delivery (4)

A
  • coatings can be applied to control diffusion rates and modify the release properties of the drug from the interior
  • disintegrates 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 as swellable matrices, non-swelling matrices, and inert plastics
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2
Q

coating (5)

A

applied to the outside of solid dosage forms to accomplish (1) protection of agent from air and/or humidity, (2) mask taste, (3) provide special drug release, (4) aesthetics, (5) prevent inadvertent contact with drug

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3
Q

aqueous film coatings generally contain (4)

A

(1) film-forming polymer
(2) plasticizer to produce flexibility and elasticity of coating
(3) colorant and opafier
(4) vehicle

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4
Q

enteric coating

A

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

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5
Q

the primary reasons for enteric coating (5)

A
  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
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6
Q

sustained release

A

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. the onset of pharmacologic action is delayed, but its therapeutic effect has a sustained duration

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7
Q

controlled release

A

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

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8
Q

examples of traditional controlled release formulations - coated beads, granules, or microspheres

A

coating on the beads control release by programmed erosion - example = contact

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9
Q

examples of traditional controlled release formulations - multitablet system

A

small tablets placed in a gelatin capsule

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10
Q

examples of traditional controlled release formulations - microencapsulated

A

solids, liquids, or gases ar encapsulated into walled material, which allows spreading of microparticles across absorbing surface

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11
Q

examples of traditional controlled release formulations - drug embedding in a slowly eroding or hydrophilic matrix

A

drug is homogeneously dispersed in the eroding matrix and its release is controlled by erosion rate

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12
Q

steady state

A

the rate going into the body must equal the disposition (the rate distributing early and being metabolized, and/or being excreted rom the body throughout) - image slide 10

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13
Q

characteristics of drugs best suited for oral controlled release formulation (5)

A
  • exhibit neither slow or fast rates of absorption and excretion
  • uniformly absorbed from the gastrointestinal tract
  • administered in relatively small does
  • have good safety/therapeutic window
  • chronic therapies better suited than acute
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14
Q

physiological factors affecting absorption (7)

A
  1. absorbing surface area
  2. residence time at absorption site
  3. pH changes in lumen
  4. permeability/(perfusion) - functional and molecular characteristics of transporters and metabolism
  5. dietary fluctuations/effects
  6. complexation/protein binding
  7. biliary uptake and clearance
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15
Q

epithelia (4)

A
  • predominantly used for external surfaces although endothelial cells are epitheliod
  • they sit on a layer of extracellular matrix proteins, e.g. collagen and fibronectin, termed the basal lamina
  • epithelial cells are polarized, with directional transport
  • endothelial cells line inside surfaces of body cavities
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16
Q

several different types of epithelia (4)

A
  1. simple squamous-thin layer of flattened cells that are relatively permeable. lines most blood vessels-placenta, endothelial cell
  2. simple columnar (GI tract)
  3. translational - comprised of several layers with different shapes (required to stretch)
  4. stratified squamous-multiple layers of squamous cells that cover areas subject to wear and tear (ex: skin)
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17
Q

composition of biological membranes (4)

A
  • 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
  • cell membrane is a semi-permable 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
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18
Q

does cholesterol only have harmful effect on membrane

A

no - it provides fluidity at lower levels. exceeds certain level in membrane = membrane undergoes a phase transition and forms a liquid crystalline state (hardening atherosclerosis)

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19
Q

membrane and cell-based assays

A
  • permeability coefficient
  • delta Q / delta t = amount of compound appearing on the receiver side as a function of time
  • A: surface area of the filter support
  • C0 = initial concentration of compound applied to the donor side
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20
Q

intestinal transport mechanisms: passive (non-saturable)

A

paracellular (between cells) and transcellular (through cells)

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21
Q

intestinal transport mechanisms: carrier-mediated (saturable)

A

active (energy dependent) and facilitated diffusion (energy independent)

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22
Q

general interpretation of Caco-2 vs. PAMPA data

A

y axis = Caco-2 permeability
x - axis = PAMPA permeability
- above diagonal slope = absorptive influx and/or paracellular transport
- below diagonal slope = secretory and efflux transport, metabolism
- slope = permeability across lipid bilayer (passive diffusion)

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23
Q

drug transporters

A
  • drug transporter are membrane-bound proteins widely distributed throughout the body, prominently on apical and basolateral surfaces of organs involved in clearance
  • variations in drug transporter activity can be major determinants of drug response and drug safety
  • identified in adults (not as much children)
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24
Q

drug transporters physiological role

A

to move important molecules across membranes; this capacity includes moving drug molecules across membranes

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25
Q

nutrient and xenobiotic transporters: solute carrier (SLC) (4)

A
  • 43 subfamilies
  • > 300 membranes identified
  • generally influx ore secretory efflux transporters
  • PepT1, OATs, OATPs
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26
Q

nutrient and xenobiotic transporters: ATP-binding cassette (ABC) (4)

A
  • 7 subfamilies
  • 50 membranes presently identified
  • generally efflux-multidrug resistant transports
  • P-glycoprotein, MRPs
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27
Q

absorption: routes of permeability (6)

A
  1. influx transporter mediated
  2. passive transcellular
  3. passive transcellular and efflux
  4. passive paracellular
  5. metabolism
  6. efflux of the metabolite(s)
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28
Q

conventional terminology (4)

A
  • influx transporters transfer substrates into cells’
  • efflux transporters pump substrates out of cells - absorptive transporters transfers substrates into the systemic blood circulation
  • secretory transporters transfer their substrates from the blood circulation into bile, urine, and/or GI lumen
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29
Q

passive paracellular permeation (5)

A
  • 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
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30
Q

facilitative/active transcellular permeation (5)

A
  • 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 o efflux by Pgp or BCPR
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31
Q

passive transcellular permeation (5)

A
  • lipophilicity (hydrogen bonding potential and hydrophobicity)
  • molecular size and shape
  • pKa of the ionizable groups
  • linear increased in permeability with increasing concentration
  • dissolution/solubility limit with high lipophilicity
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32
Q

GI tracts epithelia - oral cavity

A

bussal (Stratified squamous epithelium) and sublingual (simple squamous epithelium)

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33
Q

GI tracts epithelia - esophagus

A

stratified squamous epithelium

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34
Q

GI tracts epithelia - trachea

A

pseudostratified squamous epithelial cells

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35
Q

GI tracts epithelia - stomach

A

columnar epithelia cells and mucus producing goblet cells and parietal (acid secreting) and enterochromaffin-like (histamine screting) cells

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36
Q

GI tracts epithelia - small and large intestines

A

columnar epithelial cells (absorption)

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37
Q

GI tracts epithelia - rectum

A

upper (simple columnar) and lower (stratified squamous non-keratinized transitioning to stratified squamous keratinized region near anal sphincter)

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38
Q

role of the stomach (5)

A
  1. to digest food and control the flow of its contents into the intestine
  2. acts as a food reservoir
  3. processes food into fluid chyme for nutrient absorption
  4. regulates food delivery to intestine
  5. pH protects against most bacteria, allows pepsin to function
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39
Q

organization of stomach (3)

A
  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
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40
Q

stomach facts (5)

A
  • fasted pH = < 3
  • fed pH = 5-7
  • gastric emptying half-time = about 30 min
  • fasted emptying cycles through 4 phases culminating with a “Housekeeper” wave
  • fed state, no defined cycle
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41
Q

phases of stomach

A

slide 44 part 1

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42
Q

intestine facts (5)

A
  • 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
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43
Q

intestine characteristics (4)

A
  1. most transporters are located in SI
  2. upper SI = mixing
  3. lower SI = electrolyte
  4. colon = fluid and electrolyte absorption
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44
Q

intestinal absorbing surface area

A

area of cylinder = 1
folds of kerckring X 3
villi X 30
microvilli X 600
increases in surface area in the small intestine = due to folding

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45
Q

relative size of micro vs. nan particles

A

110 nm will get trapped in MV even though nan is smaller than micro

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46
Q

columnar epithelium

A
  • columnar eptihelia cells form a single continuous layer of absorptive cells ( 25 micrometers high and 8 micrometers wide) covering each villus
  • separated from lamina propria (blood vessels and lymph( by basal lamina- 300A thick- comprised of glycoproteins and penetrable by lymphocytes
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47
Q

columnar epithelium cyrpt region

A
  • 3x more crypt than villa
  • comprised of undifferentiated cells that proliferate
  • goblet cells-mucus secreting; paneth cells-regulate microflora; and argentaffin cells that secrete mucus component
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48
Q

columnar epithelium villus region

A
  • 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 of at the tip-enterocyte lifetime 2-3 days, entire lining o the GI tracts turns over every 2-4 days
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49
Q

colon characteristics (4)

A
  1. 125 cm long from caecum to anus, with transport being much slower than in small intestine (ascending colon 20 cm long, transverse colon 45 cm long, descending colon 30 cm long-rest is sigmoid)
  2. varies in thickness from 2.5 cm in the sigmoid region to 8.5 cm in the caecum
  3. ileocaecal valve limits food flow from the ileum into the caecum and vice-verse
  4. responsible for water and electrolyte absorption (caecum, ascending colon) - prevents dehydration and leads to formation of solid fecal matter
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50
Q

colon structure

A
  • serosa-squamous epithelium covered with adipose tissue
  • muscularis externa-inner circular muscle layer and incomplete outer longitudinal layer
  • submucosa and mucosa
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51
Q

colonic mucsoa - three layers

A
  1. muscularis mucosae
  2. lamina propria
  3. epithelium
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52
Q

proximal colon is usually where…

A

enteric coated formulations target by oral administration

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53
Q

as you get older, you aren’t excreting as much which can affect…

A

drugs that need to move through the colon if necessary

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54
Q

label remaining in region (%) vs. time (min) - deck 2 - slide 70

A

review

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55
Q

rectum (5)

A
  • highly folded
  • stratified squamous, non-keratinized epithelium, in particular, allows high drug absorption
  • number of high potency drugs that may be delivered rectally
  • young and old patients have gag reflex problems with pills, extemporaneous compounding of the drug in suppositories is used
  • low residence time
56
Q

general consideration for oral absorption deck 2 - slide 74

A
  1. disintegrations/deaggrergation of particle –> dissolution
  2. crystalline form- low solubility OR amorphous-increased solubility
  3. free API
  4. intestinal flora or bile or nucelate or potential confounders are food, pH, protein bindings, etc
  5. absorption
57
Q

GI characteristics in Man UPDATE slide 75

A

correlates with drug release??

58
Q

GI transit time variation

A
  • gastric residence differs dramatically
  • gastric emptying controls colonic absorption, where greater GI residence leads to higher absorption
  • eating before or after you take a pill can affect the absorption rate/where it is absorbed
59
Q

characterization of GI luminal fluids

A
  • jejunum = pH 7.08 plus/minus 0.54, buffer capacity 3.23 plus/minus 1.26, bile salt content 2.88 plus/minus 1.8
  • ileum = pH 7.8, buffer capacity 6.4
  • colon = pH 8.1 plus/minus 0.53, buffer capacity 36.2 plus/minus 7.92
60
Q

drug solubility changes along the GI tract: factors (5)

A
  1. buffer capacity
  2. bile sats
  3. regional fluids
  4. other drugs
  5. potential issues rom endogenous substrates
61
Q

luminal transit - deck 2 - slide 82

A
62
Q

challenges to assumptions made with GI physiology - clinical considerations (6)

A
  1. transporters & enzymes vary along the GI tracts
  2. variability is enormous in GI fluid composition
  3. diet and chemical exposure varies
  4. pharmacogenetics & genomics are huge issues
  5. interindividual variation is also significant (intra?)
  6. drug-nutrient & drug-drug interactions are common
    bottom line = one size formulatiolns do not it all
63
Q

biopharmaceutical processes & toxicity (ADMET)

A
  • 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
64
Q

drug fate upon administration

A

deck 2 - slide 87

65
Q

nature of pharmacokinetic processes (5)

A
  • described by concentration time profiles (shape of the profiles depends point of observation) - compartments represent kinetically similar tissue or spaces
  • processes can be reversible or irreversible
  • processes an be linear or nonlinear
  • fast and slow processes tend to “disappear”
66
Q

typical blood level vs. time curve

A

increase = absorption
max point = Cmax, Tmax
decreasing
1. distribution, metabolism, excretion
2. disposition phase
3. elimination phase

67
Q

bioavailability

A

the rate and extent of drug absorption

68
Q

absolute bioavailability

A

the AUC of a given dosage form compared with the AUC of the same dose injected intravenously

69
Q

relative bioavailability

A

the AUC of a given dosage form compared to an arbitrary reference standard

70
Q

bioequivalent

A

dose not mean that the therapeutic effect of two dosage forms are equivalent

71
Q

the concept and use of DOSE

A
  • covers 2 aspects: (1) the amount of chemical in which the whole organism is treated and (2) the local concentration of the chemical at the biological response site
  • relationship between dose and receptor concentration is a function of the ADME
  • dose-response relationship is the most important factor in pharma- and toxicology
72
Q

framing slide - what we are trying to dissect in dosage form design - slide 97

A

absorption begins declining as disposition begins to increase

73
Q

minimum toxic level and minimum effective level graph slide 98

A
74
Q

relationship between dose and toxic response

A

toxic response, safe and efficacious, not efficacious

75
Q

site of drug metabolism

A

first pass metabolism
- GI epithelium
- liver
systemic metabolism
- can occur in organs and in the blood stream

76
Q

classes of metabolism

A

phase 1: metabolism of the main compound - examples: decarboxylases, oxygenase, deamidation
phase 2: metabolism through addition, conjugation - examples: glucuronidation, sufation
phase 3: transport - multidrug resistance

77
Q

**the objectives of drug metabolism (2)

A
  1. to eliminate the pharmacological activity of drug
  2. to make a compound continuously more soluble until it cannot escape excretion, potentially by more then one route
    goal = always make more soluble
78
Q

**these objectives could be accomplished by (4)

A
  1. change the molecule’s shape to block its binding to receptors
  2. change the molecule’s lipophilic character to a more hydrophilic character and increase solubility
  3. increase the molecule’s size so it is more readily cleared by the bile or the urine
  4. to make the molecule more recognizable by efflux pumps to increase its elimination from target organs and excretion in bile and urine, etc.
79
Q

metabolism of tamoxifen (prodrug)

A

TAM –(CYP3A4) –> NDM –(CYP2D6) –> 4OH-NDM

80
Q

drug metabolism

A

metabolic enzymes evolved as a defense mechanisms to highly lipophic, aromatics that naturally occur in the environment (e.g., phytoestrogens in plants) or we are exposed to through daily life (e.g., polycyclic aromatic hydrocarbons that come from burning of items)

81
Q

drug metabolism CYPs (3)

A
  • for phase 1 metabolism, a majority of focus is on the cytochrome P450 family and in particular CYP3A4
  • 1 CYPs in humans, with CYP3A5 now being considered to metabolize many of the compounds that were thought to be primarily through CYP3A4
  • CYPs are grouped into families, where 2 CYPs having about 40% amino acid homology are considered to be in the same family. there are roughly 70 mammalian CYPS
82
Q

nonlinear PK leads to nonlinear TK - slide 13

A

accumulation/saturation (top)
stead state (middle)
induction (bottom)

83
Q

processes required for oral absorption of monolithic dosage forms (4)

A
  • 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 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
84
Q

effect of particle size (3)

A
  • surface area increases when solids are broken up into smaller pieces
  • effect continues as you move from tablet to granules to particles
  • increased surface area leads to increased dissolution rate
85
Q

rate of dissolution

A

the change in the amount of mass that appears in solution over time

86
Q

rate of dissolution depends on… (5)

A
  1. D - diffusion coefficient (Fick’s 1st)
  2. S - surface area of tablet/granules available to donate drug to solution
  3. h - thickness o stationary layer
  4. Cd = concentration of drug in the donor (x = 0)
  5. Ca = concentration of drug in bulk solution (x=h)
87
Q

noyes-whitney (3 big ideas and 1 subtopic idea of each)

A
  1. dissolution rate = proportional to D
    • increased rate of diffusion = increased dissolution
  2. dissolution rate = proportional to tablet/particle surface area
    • increased are for drug to diffuse away rom solid
  3. dissolution rate is proportional to the difference in the concentration gradient
    • remember La Chatelier’s Principle = molecules want to move from high to low conc.
88
Q

dissolution rate is inversely proportional to h

A
  • increased h means a less steep concentration
  • assuming equal D it will take more time for a molecule to move to bulk concentrations
  • can decrease h by increasing stirring rate (increased stir rates lead to increased dissolution rate)
89
Q

permeability (4)

A
  1. similar but different than dissolution
  2. diffusion across a barrier instead of across an unstirred layer
  3. meed to include partition coefficient (K) to account for the changes in environment between inside and outside of barrier ( water vs. hydrophobic core of membrane
  4. can remove Ca if we assume sink conditions - concentration in membrane is negligible compared to GI fluids
90
Q

D =

A

diffusivity

91
Q

S =

A

surface area of the boundary (GI surface area)

92
Q

K =

A

partition coefficient (solubility inside barrier divided by solubility outside barrier)

93
Q

Cd =

A

donor (GI) concentration

94
Q

h =

A

thickness of barrier (thickness of GI cell membrane)

95
Q

P = (DK)/h =

A

permeability

96
Q

3 factors can limit the ability of a drug to absorb after oral administration

A
  1. solubility - can’t get enough drug into solution
  2. dissolution - can’t get drug out of tablet
  3. permeability - can’t get drug across GI cell membrane
97
Q

solubility limited (4)

A
  • 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
98
Q

dissolution limited (4)

A
  • drug = unable to dissolve into the solution from the dosage form in sub-saturated fluid
  • dissolution time is greater than the time or absorption in the intestines
  • often due to poor formulation/manufacturing
  • need to have a tablet that can dissolve but also stand up to shilling and handling
99
Q

permeability limited (3)

A
  • characteristic of the API itself similar to solubility limited
  • dissolution is fast with sub-saturated fluids
  • increasing the amount of drug increases absorption
100
Q

solubility/dissolution graphs

A

deck 3 - slide 26

101
Q

factors limiting oral drug absorption: solubility

A
  • physicochemical constraints: dissolution is fast & permeability is fast
  • observations: gut is saturated by a high dose. absorption dose not increase with increased dose
102
Q

factors limiting oral drug absorption: dissolution limited

A
  • physicochemical constratins: Tdiss is greater than residence time in small intestine & permeability is fast
  • observations: dissolution can be enhanced by particle size reduction. absorption increases with increasing dose
103
Q

factors limiting oral drug absorption: permeability limited

A
  • physicochemical: permeability low regardless of the solubility. dissolution
  • observations: amount of drug absorbed increases with increased dose
104
Q

generic drug

A

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

105
Q

generic product: therapeutic equivalance

A
  • pharmaceutical equivalence and bioequivalence
106
Q

pharmaceutical equivalents

A

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

107
Q

generics and therapeutic equivalence

A

slide 41 - toxic level vs. therapeutic level

108
Q

questionnaire-based study assessing switch to generic formulation of the same drug product

A
  • 2885 patients
  • 70.5% no problem after switch
  • 10.8% range of problems including reappearance of seizures
  • 8.8% other issues, but no follow-up included
  • 30% of respondents reported an issue with a witch to a generic - they are not interchangable!
109
Q

bioequivalent - a closer look (2)

A

a drug product is considered bioequivalent if the 90% confidence interval of the rations 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]
- difference in Cmax and Tmax were due to faster dissolution of the generic products comparative to the RLD

110
Q

IVIVC

A
  • 4 products demonstrate linear relationship between % dissolved & % absorbed
  • no single correlation could be established to predict the bioavailability of all four products
  • no correlation was possible between dissolution rate and AUC
111
Q

mimicking clinical conditions (4)

A
  1. dosage form design requires consideration of patient related variables
  2. patient related variables are not accurately assessed during development and scale up
  3. “absorption windows” are defined more based on physical chemical properties and not physiology
  4. better in vitro an in vivo testing models are required or optimizing dosage form design and scale-up
112
Q

**oral delivery summary (5)

A
  1. drug performance (PK/PD) is controlled by the interplay of excipients (formulations), the physicochemical properties od the drug, and the physiological barriers between the GI tract and the site of action
  2. oral formulation can control the absorption rate (Kabs), which then has to be optimized with respect to disposition to yield a safe and efficacious response
  3. dosage form design is dynamic and is unpredictable, so patient habits have to be considered for dosing regimens
  4. patients will vary in response, so this needs to be considered
  5. generic formulations are not the innovator, and thus can cause some problems with performance
113
Q

pharmacotherapy and pregnancy (3)

A
  • roughly 60 million women at reproductive age
  • roughly 10% of these women become pregnant annually
  • but… PK of drugs in pregnancy is complex - physiological changes alter ADME of drugs and toxicity is a significant concern
114
Q

fetal imprinting (2)

A
  • the developing fetus undergoes rapid changes during the 9 month gestation period
  • genetics, diet, environment, etc. can all impact the fetus
115
Q

fetal imprinting linked to (3)

A
  1. cardiovascular disease - Baker Hypothesis
  2. neurological disorders
  3. obesity/diabetes, as well as others
116
Q

fetal imprinting: very difficult to predict human effects based on… (2)

A
  • many factors involved aside from genetics, e.g., diet
  • many exposure studies done in animals
117
Q

other pediatric pharmacology issues (5)

A
  • historical cases with drugs like thalidomide in the 1950s indued in utero malformations
  • exposure to xenobiotics are poorly understood. for example, endocrine disrupting chemicals 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
118
Q

pediatric drug development

A
  • early USA regulation - 1962 Keauver-Harris Drug Amendments required efficacy and safety demonstration for FDA approval and marketing
  • legislative incentives/mandates (3) in place to promote pediatric development
119
Q

best pharmaceuticals in children act

A

testing drugs in children presents considerable scientific, clinical, ethical, technical, and logistical challenges
- incentives for companies to study drugs in neonates, infants, and the children
- technology to monitor patients and assay very small amounts of blood
- suitable pediatric clinical infrastructure for drug trails

120
Q

pediatric pharmacology

A
  • children are “therapeutic orphans”
  • only 20-30% of approved drugs have pediatric labeling
  • FDA has encouraged pediatric studies (financial incentives, increase study results, approval of selective number of new drugs)
121
Q

pediatric pharmacology: descriptive pharmacology in pediatric patients is often lacking (4)

A
  1. children are not “miniature adults” - dosing based on scaling (by body weight or body surface area) not always predictable for a given drug
  2. animal studies not always predictive
  3. clinical studies in children fraught with ethical an financial hurdles
  4. administration of drug can also be problematic
122
Q

pediatric biopharmaceutics classification system (PBCS) (2)

A
  • the BCS = widely used to expedite generic and drug repurposing formulations for industry
  • there is an urgent need to expedite the development of pediatric formulations
123
Q

classification is based on three factors that influence the drug’s bioavailability form a peroral formation:

A
  1. solubility (in vitro, biorelevancy)
  2. intestinal permeation across the intestinal barrier (in vitro vs. in vivo, regional)
  3. dissolution rate (in vitro, biorelevancy)
124
Q

our joint NICHD-FDA task force tentatively proposed the following BCS classification

A
  • class 1: (pediatric, volume = 25 ml): rapid dissolution (t50 = 15 min.) for immediate release
  • class 2: (subclasses a, b, c, for acidic, basic and neutral drugs); dissolution criteria are critically needed
  • BCS class 3: very rapid dissolution
  • BCS class 4: same as BCS class 2
125
Q

OATP1B1 SNP and methotrexate (MTX) - slide 74

A

low clearance rates are associated with higher toxicity. dose lowering adjustments and higher hydration rates should be required in children carrying these phenotypes

126
Q

extrapolation between species

A
  • the relevance of animal models (differences in the developmental timing o anatomical, physiological, biochemical and the 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
127
Q

emerging topics in pediatric drug transporter research

A
  1. actors govern regulation of transporter expression and activity during growth and development
    • nuclear receptor regulation and endocrine changes
  2. genetic variations add to age-related variations in drug transporter expression and function
  3. impact of disease, drug-gene interactions, drug-drug interactions, food-drug interactions, and exposure to environmental chemicals on the expression and function of drug transport proteins
128
Q

challenges with pediatrics

A
  • biological challenges = ontogenic and compositional changes
  • clinical challenges = clinical trials and caregiver requirements
  • formulation challenges = dosage form selection, flexibility in dosing, excipient selection, and taste masking
129
Q

pediatric drug development initiatives

A
  • paradigm shift for industry
    old = protect children from clinical research
    new = protect children through clinical research
130
Q

new challenges based on paradigm shift (4)

A
  1. children are not miniature adults
  2. pediatric patients need to be age classified
  3. pediatric patients require age appropriate formulations that used to be primarily made through compounding
  4. first in child safety and efficacy preclinical models are lacking
131
Q

pediatric formulations

A
  • the safety and toxicology of excipients for pediatrics database
    • collab 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
132
Q

mini-table platform formulation

A
  • ability to incorporate BCS class I and III (less effect of formulation & likely more beneficial for testing of mediations already on the market)
  • easy translation to market formulation (peds compliance, flexible dosing, and protected from degradation of vehicle or stomach)
  • minimal excipients (single filler, disintegrant, lubricant with functional coatings
  • same or similar manufacturing conditions (same size is constant, number can fluctuate)
  • fractional factorial DOE approach (many process and formulation variables)
133
Q

pharmaceutical film considerations: advantages (5)

A
  1. acceptable for patients with dysphagia
  2. ease and accuracy of dosing
  3. increased stability compared to solutions/suspensions
  4. faster onset of actions
  5. life cycle management
134
Q

pharmaceutical film considerations: disadvantages (4)

A
  1. difficult to manufacture
  2. moisture sensitive
  3. limited dosing capacity
  4. increased packaging costs
135
Q

pediatric pharmacology - challenges remain UPDATE

A
  • age based dosage orm selection
  • need for descriptive pharmacology in peds

PHRM 828 exam 2 (1 decks)

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