Knipp 3

Question 1

Drug metabolism purpose

Answer 1

to eliminate pharmacological activity of a drug
to make a compound continuously more soluble until it cannot escape excretion
TO DO SO:
change molecule’s shape to block binding
change molecule lipophillic character to more hydrophillic to increase solubility
increase molecule size so it is more cleared by bile/urine
make moleucle more recognizable by efflux pumps to increase elimination

Question 2

sites of drug metabolism

Answer 2

first pass: GI epithelium and liver
systemic: occurs in all organs and in blood stream

Question 3

classes of metabolidm

Answer 3

phase 1: metabolism of the main compound. decarboxylases, oxygenases, deamindation.
phase 2: metabolism through addition, conjugation, glucuronidation, sulfation
phase 3: transport-multidrug resistance

Question 4

metabolism of tamoxifen

Answer 4

TAM w/ CYP3A4 -> NDM w/ CYP2D6 -> 4OH-NDM
TAM w/ CYP2B6 -> 4OHT w/ 3A4 -> 4OH NDM(endoxifen)

Question 5

drug metabolism CYPs & enzymes

Answer 5

enzymes evolved as defense for highly lipophilic aromatics like phyoestrogens in plants + polycyclic hydrocarbs from fire
phase 1: main focus is CYP450
CYPs are grouped into families where two CYPs have ~40% AA homology

Question 6

nonlinear PK lead to nonlinear TK

Answer 6

accumulation/ saturation lead to side effects
induction leads to less therapeutic response

Question 7

Processes required for oral absorption of monolithic dosage forms

Answer 7

drug molecules at surface dissolve to form saturated solution
dissolved drug molecules pass through dissolving fluid from high to low conc.
drug molecules diffuse through bulk solution to absorbing mocosa are absorbed
replenishment of drug molecules in diffusion layer is acheived by further dissolution

Question 8

effect of particle size

Answer 8

surface area increases when solids are broken to smaller peices which increases absorption
effect continues as you move from tablet to granules to particles
increase SA is increase dissolution rate

Question 9

dissolution

Answer 9

rate of dissolution: change in amount of mass that appears in solution over time
dependent on:
D - diffusion coefficient
S - SA
Cd - concentration of drug in donor
Ca - concentration of drug in bulk solution

Question 10

Noyes-Whitney

Answer 10

dissolution rate is proportional to D and tab/particle SA
dissolution rate is proportional to difference in concentration gradient
dissolution rate is inversely proportional to h:
increasing h means a less steep concentration gradient

Question 11

permeability

Answer 11

similar but different than dissolution
diffusion across barrier instead of across unstirred layer
needs partition coefficient K
D - diffusivity
S - SA of boundary (GI SA)
K - partition coefficient
Cd - donor (GI) concentration
h - Thickness of barrier (GI thickness)
P - DK/h = permeability

Question 12

factors limiting oral drug absorption

Answer 12

3 factors:
solubility - cant get enough drug into solution
dissolution - cant get drug out of tablet
permeability - cant get drug across GI cell membrane

Question 13

solubility limited

Answer 13

drugs w/ poor solubility are often limited as dug candidates
represented as a small Cd value in previous equations
dosage form dissolves fast and drug permeates readily
increasing dose doesnt increase blood levels as GI fluids are already saturated
bigger molecules - decrease solubility

Question 14

dissolution limited

Answer 14

drug is unable to dissolve into solution from dosage form in sub-saturated fluid
dissolution time is greater than time for absorption in intestines
due to poor manufacturing/formulation
need to have tab that can dissolve but withstand shipping and delivery

Question 15

permeability limited

Answer 15

characteristic of API
now barrier is getting through intestinal wall
dissolution is fast w/ sub-saturated fluids
increasing amount of drug increases absorption
increase Cd by increasing amount of drug
increase dM/dt which is absorption

Question 16

solubility/dissolution

Answer 16

permeability rate limited: drug in solution is high, solid drug is low. rate limiting factors - physiochemical properties (drug) and physiological prop (membrane)
dissolution rate limited: solid drug high, drug insolution low. rate lim factors - physicochemical(drug + formulation)

Question 17

generic drug definition

Answer 17

a drug product that is comparable to a brand/reference listed drug product on dosage form
generic drug product: therapeutic equivalence- pharmaceutical and bioequivalence
generic product judged therapeutically equivalent to reference drug

Question 18

pharmaeceutical equivalence

Answer 18

same active ingredients; dosage form; route of administration; strength/concentration.
may differ in looks

Question 19

bioequivalence

Answer 19

pharmaceutical equivalents whose rate and extent of absorption are not statistic different when administered to humans at the same dose

Question 20

generics and therapeutic equivalence

Answer 20

two graphs have same AUC, but one does not reach therapeutic window

Question 21

assessing switch to generic

Answer 21

70.5 % no problems after switch
30% respondents reported an issue with a switch to generic

Question 22

meyer study

Answer 22

a drug is considered bioequivalent id it is in 90% confidence interval,
so AUC and Cmax within 80-125%
differences in Cmax and Tmax were due to faster disolution of generic compared to RLD

Question 23

IVIVC

Answer 23

generics were a lot steeper slope than the RLD so they were not interchangeable products

Question 24

***Mimicking clinical condition

Answer 24

dosage form design requires consideration of patient related variables
patient related variables are not accurately assessed during development and scale up
absorption windows are more defined based on physical and chem properties
better in vitro and in vivo testing models are required for optimizing dosage form

Question 25

***Oral delivery summary

Answer 25

drug performance (PK/PD) is controlled by the interplay of excipients, physicochemical properties of the drug, and barriers between GI and site of action
oral formulations can control the absorption rate (Kabs) which needs to be optimized
dosage form design is dynamic and unpredictable so patient habits are considered
patients will vary in response
generic formulations are not the innovator, so they can cause performance problems

Question 26

pharmacotherapy and pregnancy

Answer 26

60 mil women at reproductive age
10% become pregnant annually and are on meds for chronic illness
PK of drugs during pregnancy is complex –> changes in ADMET of drugs and toxcity
placenta can be male

Question 27

fetal imprinting

Answer 27

developing fetus has rapid changes in 9 months
genetics diet environment is important
fetal imprinting linked to cardiovascular disease, neurological disorders, obesity

Question 28

other PED pharmacology issues

Answer 28

thalidomide in caused in utero malfunctions
exposure to xenobiotics caused in utero programming of cancer
xenobiotic exposure can lead to PK/PD changes

Question 29

PED drug development

Answer 29

early USA regulation 1962 - amendments required efficacy and safety for FDA approval
legislative incentrives to promote pediatric development

Question 30

best pharmaceuticals in children act

Answer 30

testing drugs in children have lots of challenges which discourages it
act incentives for companies to study drugs in neonates, children, infants
tech to monitor patients and assay very small amounts of blood
pediatric clinical infrastructure

Question 31

pediatric pharmacology approved drugs

Answer 31

children are theapeutic orphans
20-30% of approved drugs have pediatric labeling
FDA encourage pediatric studies

Question 32

pediatric pharmacy

Answer 32

descriptive pharmacology is lacking in pediatric patients:
children are not mini adults
animal studies arent always predictive
clinical studies in children fraught w/ ethical and financial hurdles
administering drugs can be a problem

Question 33

PED biopharmaceutics classification system (PBCS)

Answer 33

BCS has been used to expedite generic and drug repurposing formulations
classification is based on 3 factors: solubility, intestinal permeation, dissolution rate
urgent need to expedite PED formulation
disposition drives safety and efficacy

Question 34

PBCS class system

Answer 34

Class 1: rapid dissolution for immediate release
Class 2: dissolution criteria are critically needed
Class 3: very rapid dissolution
Class 4: same as BCS class 2

Question 35

extrapolation between species

Answer 35

the relevance of animal models can limit extrapolation to humans
length of gestation and timing of events + relative organ function maturity
significant species differences exist in transport protein and machinery

Question 36

pediatric drug transporter research

Answer 36

what impacts growth and development? - nuclear receptor regulation + endocrine changes
do gene variation add to age variation

Question 37

PED challenges

Answer 37

CYP3A4 not in children
bio: ontogenic + compositional challenges
clinical: clinical trials + caregiver requirements
formulation: dosage form selection, flexibility in dosing ,excipeint selection, taste masking

Question 38

PED drug development initiatives

Answer 38

protect children through clinical research
children are not mini adults
PED patients need to be age classified and age appropriate formulations

Question 39

PED formulation

Answer 39

safety and toxicology of excipients for PED database
encourages solid dosage form
draws attention to use of traditional excipients

Question 40

mini tablet

Answer 40

ability to incorporate BCS class 1 + 3
more beneficial for testing meds on market
pediatric compliance, flexible dosing, protect from degradation
minimal excipients, size is constant

Question 41

pharmaceutical film considerations

Answer 41

advantages: acceptable for patients w/ dysphagia, ease and accuracy of dosing, stability, faster onset, life cycle management
disadvantages: difficult to manufacture, moisture sensitive, limited dosing capacity, increased packaging costs

Question 42

***PED pharmacology, challenges remain

Answer 42

age based dosage form selection
need for descriptive pharmacology
children are not mini adults
animal models need to be refined
enable clinical studies by looking at ethical + financial hurdles
better means of drug administration are needed