Final Flashcards
What is a generic?
copies of brand-name drugs with the same active ingredient and same intended therapeutic use as innovator product.
Main 2 differences of a generic and innovator?
Cheaper
look different
What was the most different in product performance due too?
dissimilar Cp vs t
impaired absorption and F
Thalidomide tragedy?
used for morning sickness
caused birth defects, d/c in 1961
What was added in 1962 to the Federal Food Drug and Cosmetic Act?
Proof of efficacy
generics had to meet saftey, efficacy, and bioequivalence
What was seen with generics with the new additions in 1962 too the FFDCA?
Not done, cost of clinical trials to get to market to high
What was added in 1984 to help generic market?
Drug Price Competition and Patent Term Restoration act (Hatch-Waxman Act)
What did the Hatch-Waxman act do?
established abbreviated new drug application procedure
- approval of generics of drugs already safe and effective
- only needed to meet pharmaceutical and bioequivalence
what % of Rx’s are substituted to generics?
~70%
Are generic drug companies liable for failing to list side effects?
No, if they copy the exact same warnings as brand-name equivalents
Do generics need to contain the same non-medicinal ingredients?
no
Can TPD bioavailability definition?
rate and extent of absorption of a drug into systemic circulation
Basic assumption of bioequivalence?
products are assumed therapeutically equivalent and interchangeable
Factors related to the dosage form?
physiochemical properties of the drug:
- particle size
- crystalline structure
- polymorphic form
- degree of hydration
- salt form
- ester form
Formulation and manufacturing variables:
- amount of disintigrant/lubricant
- coatings
- nature of diluent
- compression force
Factros related to the pt?
Physiological factors
Interactions with other substances
Difference of Absolute and Relative bioavailability?
absolute uses IV and oral
relative uses 2 different dosage forms that follow same RoA
Extent of F equation for single dose?
AUC(test drug product) x D(standard drug product
————————————————
AUC(standard drug product) x D(test drug product)
all x 100
Extent of F for multy dosing?
AUC(tdp) x D (sdp)/AUC(sdp) x D(tdp) x100
AUC uses complete tau
What is the same with the rates of bioavailability?
AUC
elimination rate constant
complete absorption for all formulations
What is different with the rates of bioavailability?
Onset
duration of effect
intensity
what are indicators of rate of bioavailability>
Tmax and Cmax
ROB formula?
AUC(+ vehicle;granules;tablet) / AUC(solution)
x100
What is the true rate constant?
absorption rate constant from solution
WHat is the apparent rate constant?
Absorption rate constant from drug product
When is bioequivalence required?
new generic
an innovator manufacturer to show product to be marketed is BE with formulation used in pivotal clinical trials
If innovator manufacturer cahgnes the formulation of a drug already on the market or new dosage strengths
When considering new route of admin
When is a waiver of bioequivalence allowed?
solution intended for IV use
topically applied for local use
oral dosage form not intended to be absorbed
inhaled drug
solution, elixer, syrup, tincture form of an approved product and contains no inactive ingredient known to affect BA
Waiverfor Class I BCS drugs
Order of preference of Bioequivalence studies?
PK-BE
PD-BE
Comparative clinical study
In Vitro
Dissolution study
Biopharmaceutics classification system (biowaivers)
When is a PD-BE used?
when PK approach is not possible (locally acting drug product)
PD parameters?
AUC of the PD effect vs time
Peak PD effect
time for peak PD effect
Uses a pharmacological or clinical endpoint
What kind of study is used in clincial studies for BE?
blind or double blind
What concept of BE does PK-BE use?
Exposure concept;
total exposure (AUC –> infinity for single, to tau for multy)
Peak exposure (Cmax)
Early exposure (partial AUC to peak time)
What ethics parameters are needed for BE testing?
institutional human ethics review
informed consent
pre and post study physical exams
medical history done pre-study
What 3 statistical concepts should always be considered when looking at a study design?
randomization
replication
error control
What is a typical single oral dose study design?
2 products, 2 periods, 2 sequence, crossover w/ washout period
Benefit of a crossover design?
diminishes intersubject variation and allows for examination of intrasubject variation
What do you need to do in a parallel design to coutneract the non-within-subject comparison?
increase number
whenvis parallel design considered/
drug has very long t1/2
some depot formulations
What does the number of subjects depend on?
Significance level of:
mean difference between T and R (usually +/-20%)
intra-subject variance
power (typically 0.8)
type 1 error rate of 5%
Minimum number of subjects for a study?
12
Standardized study conditions?
Diet
exercise
smoking
alcohol use
psoture
other drug use
blinding is done
control food and fluid admin
dose taken with standard volume of water at standard temp
water and food 1 and 4 h before/after dose respectively
how many samples should be collected per subject per dose?
12
How many t1/2 should you sample for?
atleast 3
Advantages of multy dose design?
dont need to extrapolate for AUC
more closely related to clincial use of drug
allows Cp measured at therapeutic levels
can detect nonlinear PK
Disadvantages of multy dose design?
more time and more difficult
more costly
issues with compliance control
increased potential for AEs
Singl dose parameters that characterize rate and extent of F?
AUC
Cmax
Tmax
Multy dose parameters that characterize rate and extent of F?
AUC
% fluctuation
% fluctuation formula?
(Cmax -Cmin/ Cmin) x 100 (all steady state []’s)
What does the mean AUC or Cmax of T have to be within to be BE?
+/-20%
confidence interval for log-transformed data?
90% (80-125)
Confidence itnerval for the ratio of means?
90% (0.8-1.2)
3 BE comparison approaches?
Average
Population
Individual
(also population adn Individual combined)
How to pick reference product?
usually innovator
can also use standards of:
- aq true solution of drug
- aq solubolized system of the drug
- aq suspension of micronized drug
What 3 things does the comparisons for BE rely on?
criteria to base comparisons
confidence inteval for the criteria
a predetermiend BE limit
What is Cmax influenced by?
rate and extent of absorption
What is AUC value influenced by?
extent of absorption
Is testing using the nul hypothesis appropriate for BE?
No, mean differences may exist but have no clinical importance
Why is the BE range 80-125% for a 90% confidence interval?
b/c range is symmetric; 1.25 = 0.8^-1
What is the 90% GMR equation?
90%GMR = 100x e^(difference +/- t(0.05(n1+n2 - 2)xSEdifference)
What conditions should BE be demonstrated under for MR products?
fasted and fed studies
How are multiple dose MR studies preformed?
under fasting conditions
Drugs with serious toxicity within normal dosage range study design?
parallel over crossover
how many t1/2 should the test drug replace the reference drug in serious toxicity withib normal dosage range studies before sampling is done?
5+ half lives
What is the difference in BE criteria for long half life drugs?
AUC0-72 will be used as the comparison parameter
long washout periods required
What is the range for critical dose drugs?
90% CI GMR for AUC between 90-112%
Cmax still 80-125%
Class I drugs?
high solubility and permeability
Class II drugs?
low solubility
high permeability
Class III drugs?
high solubility
low permeability
Class IV drugs?
low solubility and permeability
What types of drugs are BCS-based biowaivers applicable too?
IR
solid oral dosage forms/ suspensions for systemc circulation
what is pH range used to measure the lowest solubility of the drug?
1.2-6.8 ; lowest measurement of drug solubility used in this range
at what absolute F is high permeability concluded at?
> =85%
What cells can be used to assess and validate permeability?
Caco-2 cells
Extent of absorption in relation to Class I-IV drugs?
I: very good
II: dissolution is rate limiting
III: permeability rate-limited
IV: very poor
What is rate limiting for Class I drugs?
dissolution or gastric emptying
WHy might F be low for a Class I drug?
first pass metabolism
What classes of drugs may biowaicers be probable?
Class I and III
What drug class are biowaivers not considered in?
Class IV
What are the exceptions where biowaivers are not applied to?
Narrow therapeutic range drugs
Drugs for absorption in oral cavity
when are 2 dissolution profiles considered similar?
when f2 value is >=50
WHen is comparison with an f2 test unnecessary?
when both drugs have 85% or more dissolved in 15 minutes
f2 equation?
50x log {[1 + (1/n)Sumt=1^n (Rt-Tt)^2]^-0.5 x100}
4 rights?
pt
drug
time
dose
how many cells in human body?
30-40 trillion
When are cell cycle checkpoints?
G1 and G2
Which M phase has a checkpoint?
anaphase; checks spindles
what % of human chromosomes code for genes?
10%
average chromosome amount of genes and bps?
2500-5000
130 million bps
Chromosome structure?
octomer of core histones
(H2A, H2B, H3, H4) x2
how large is mature mRNA compared to gene size?
about 1/10 in size
Nucleotide pairs?
A-T
G-C
A-U
Transcription?
gene–>mRNA
Translation?
mRNA–> protein
RNA polymerase binding site?
promoters; upstream of genes
what occurs to promoters to repress gene transcription?
methylation
how many genes in mitochondrial DNA genome?
38
4 essential parts of genomic studies?
genetic variations
gene expressions
gene regulations
gene correlations
SNP frequency?
1 in 1000 bps to 1 in100-300 bps
how many coding SNPs does each gene have approximately
5
types f CNVs?
deletion
duplication
segmental duplication
inversion
Cystic fibrosis indel?
3 bp deletion in CFTR (F508)
Huntingtons INDEL?
triplet repeat of expansions CAG in gene HTT (usually >35)
BRCA2 gene INDEL?
6.2kb deletion
Structural variation ex?
short arm of chromosome 1
hot spots for structural variation?
regions w/ lots of variation
Philadelphia chromosome?
balanced translocation of chromosome 9 and 22
leads to ALL and CML
What valuable info may SNP genotyping provide?
Drug response
Disease suceptibility
Treatmnet outcome
AE’s
Tamoxifen CYP enzyme?
2D6
P4?
predictive
preventative
personalized
participatory
how many exons in DMD gene ?
79
Eteplirsen MOA?
exon skipping therapy; skips exon 51, shortened dystrophin formed with ~50% normal function
Eteplirsen exon 48-52 look like compared to normal?
norma:48,49,50,51,52
Treated: 48,52
in DMD 49,50 are deleted resulting in early stop codon
What was the first FDA approved drug for cancer that targets genetic mutation not a cancer type?
Vitrakvi(Larotrectinib)
What is Vitrakvi indicated for?
solid tumors that test positive for NTRK gene fusions
Known acquired resistance mutations for Vitrakvi?
G623R, G696A, and F617L
Imatinib MOA?
inhibits BCR-ABL TK, proliferation
Induce apoptosis in BCR-ABL positive cells
Luminal A/B, HER2 characteristics (ER,PR,HER2)
Luminal A: ER+, and/or PR+, HER2-
Luminal B: ER+ and or PR+, HER2+
HER2: ER-,PR-, HER2+
Palbociclib?
inhibits cyclin-dependant kinases CDK4 and CDK6;
prevents cancer cells to pass the R point
Palbociclib dosing?
125mg w/ food OD x 21 day
7 days off
repeat
Tratuzumab subdomain?
IV
How does pertuzumab work?
prevents homodimerization of HER2 and heterodimerization of HER2-HER3
Combo for metastatic and recurrent HER2+ breast cancer?
Trastuzumab + Pertuzumab +docetaxel
