Knipp 3 Flashcards
Drug metabolism purpose
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
sites of drug metabolism
first pass: GI epithelium and liver
systemic: occurs in all organs and in blood stream
classes of metabolidm
phase 1: metabolism of the main compound. decarboxylases, oxygenases, deamindation.
phase 2: metabolism through addition, conjugation, glucuronidation, sulfation
phase 3: transport-multidrug resistance
metabolism of tamoxifen
TAM w/ CYP3A4 -> NDM w/ CYP2D6 -> 4OH-NDM
TAM w/ CYP2B6 -> 4OHT w/ 3A4 -> 4OH NDM(endoxifen)
drug metabolism CYPs & enzymes
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
nonlinear PK lead to nonlinear TK
accumulation/ saturation lead to side effects
induction leads to less therapeutic response
Processes required for oral absorption of monolithic dosage forms
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
effect of particle size
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
dissolution
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
Noyes-Whitney
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
permeability
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
factors limiting oral drug absorption
3 factors:
solubility - cant get enough drug into solution
dissolution - cant get drug out of tablet
permeability - cant get drug across GI cell membrane
solubility limited
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
dissolution limited
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
permeability limited
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
solubility/dissolution
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)
generic drug definition
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
pharmaeceutical equivalence
same active ingredients; dosage form; route of administration; strength/concentration.
may differ in looks
bioequivalence
pharmaceutical equivalents whose rate and extent of absorption are not statistic different when administered to humans at the same dose
generics and therapeutic equivalence
two graphs have same AUC, but one does not reach therapeutic window
assessing switch to generic
70.5 % no problems after switch
30% respondents reported an issue with a switch to generic
meyer study
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
IVIVC
generics were a lot steeper slope than the RLD so they were not interchangeable products
***Mimicking clinical condition
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
***Oral delivery summary
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
pharmacotherapy and pregnancy
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
fetal imprinting
developing fetus has rapid changes in 9 months
genetics diet environment is important
fetal imprinting linked to cardiovascular disease, neurological disorders, obesity
other PED pharmacology issues
thalidomide in caused in utero malfunctions
exposure to xenobiotics caused in utero programming of cancer
xenobiotic exposure can lead to PK/PD changes
PED drug development
early USA regulation 1962 - amendments required efficacy and safety for FDA approval
legislative incentrives to promote pediatric development
best pharmaceuticals in children act
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
pediatric pharmacology approved drugs
children are theapeutic orphans
20-30% of approved drugs have pediatric labeling
FDA encourage pediatric studies
pediatric pharmacy
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
PED biopharmaceutics classification system (PBCS)
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
PBCS class system
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
extrapolation between species
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
pediatric drug transporter research
what impacts growth and development? - nuclear receptor regulation + endocrine changes
do gene variation add to age variation
PED challenges
CYP3A4 not in children
bio: ontogenic + compositional challenges
clinical: clinical trials + caregiver requirements
formulation: dosage form selection, flexibility in dosing ,excipeint selection, taste masking
PED drug development initiatives
protect children through clinical research
children are not mini adults
PED patients need to be age classified and age appropriate formulations
PED formulation
safety and toxicology of excipients for PED database
encourages solid dosage form
draws attention to use of traditional excipients
mini tablet
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
pharmaceutical film considerations
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
***PED pharmacology, challenges remain
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
