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Final Flashcards

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1
Q

What is a generic?

A

copies of brand-name drugs with the same active ingredient and same intended therapeutic use as innovator product.

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2
Q

Main 2 differences of a generic and innovator?

A

Cheaper
look different

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3
Q

What was the most different in product performance due too?

A

dissimilar Cp vs t
impaired absorption and F

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4
Q

Thalidomide tragedy?

A

used for morning sickness
caused birth defects, d/c in 1961

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5
Q

What was added in 1962 to the Federal Food Drug and Cosmetic Act?

A

Proof of efficacy
generics had to meet saftey, efficacy, and bioequivalence

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6
Q

What was seen with generics with the new additions in 1962 too the FFDCA?

A

Not done, cost of clinical trials to get to market to high

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7
Q

What was added in 1984 to help generic market?

A

Drug Price Competition and Patent Term Restoration act (Hatch-Waxman Act)

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8
Q

What did the Hatch-Waxman act do?

A

established abbreviated new drug application procedure
- approval of generics of drugs already safe and effective
- only needed to meet pharmaceutical and bioequivalence

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9
Q

what % of Rx’s are substituted to generics?

A

~70%

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10
Q

Are generic drug companies liable for failing to list side effects?

A

No, if they copy the exact same warnings as brand-name equivalents

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11
Q

Do generics need to contain the same non-medicinal ingredients?

A

no

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12
Q

Can TPD bioavailability definition?

A

rate and extent of absorption of a drug into systemic circulation

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13
Q

Basic assumption of bioequivalence?

A

products are assumed therapeutically equivalent and interchangeable

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14
Q

Factors related to the dosage form?

A

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

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15
Q

Factros related to the pt?

A

Physiological factors
Interactions with other substances

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16
Q

Difference of Absolute and Relative bioavailability?

A

absolute uses IV and oral
relative uses 2 different dosage forms that follow same RoA

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17
Q

Extent of F equation for single dose?

A

AUC(test drug product) x D(standard drug product
————————————————
AUC(standard drug product) x D(test drug product)

all x 100

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18
Q

Extent of F for multy dosing?

A

AUC(tdp) x D (sdp)/AUC(sdp) x D(tdp) x100
AUC uses complete tau

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19
Q

What is the same with the rates of bioavailability?

A

AUC
elimination rate constant
complete absorption for all formulations

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20
Q

What is different with the rates of bioavailability?

A

Onset
duration of effect
intensity

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21
Q

what are indicators of rate of bioavailability>

A

Tmax and Cmax

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22
Q

ROB formula?

A

AUC(+ vehicle;granules;tablet) / AUC(solution)
x100

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23
Q

What is the true rate constant?

A

absorption rate constant from solution

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24
Q

WHat is the apparent rate constant?

A

Absorption rate constant from drug product

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25
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
26
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
27
Order of preference of Bioequivalence studies?
PK-BE PD-BE Comparative clinical study In Vitro Dissolution study Biopharmaceutics classification system (biowaivers)
28
When is a PD-BE used?
when PK approach is not possible (locally acting drug product)
29
PD parameters?
AUC of the PD effect vs time Peak PD effect time for peak PD effect Uses a pharmacological or clinical endpoint
30
What kind of study is used in clincial studies for BE?
blind or double blind
31
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)
32
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
33
What 3 statistical concepts should always be considered when looking at a study design?
randomization replication error control
34
What is a typical single oral dose study design?
2 products, 2 periods, 2 sequence, crossover w/ washout period
35
Benefit of a crossover design?
diminishes intersubject variation and allows for examination of intrasubject variation
36
What do you need to do in a parallel design to coutneract the non-within-subject comparison?
increase number
37
whenvis parallel design considered/
drug has very long t1/2 some depot formulations
38
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%
39
Minimum number of subjects for a study?
12
40
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
41
how many samples should be collected per subject per dose?
12
42
How many t1/2 should you sample for?
atleast 3
43
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
44
Disadvantages of multy dose design?
more time and more difficult more costly issues with compliance control increased potential for AEs
45
Singl dose parameters that characterize rate and extent of F?
AUC Cmax Tmax
46
Multy dose parameters that characterize rate and extent of F?
AUC % fluctuation
47
% fluctuation formula?
(Cmax -Cmin/ Cmin) x 100 (all steady state []'s)
48
What does the mean AUC or Cmax of T have to be within to be BE?
+/-20%
49
confidence interval for log-transformed data?
90% (80-125)
50
Confidence itnerval for the ratio of means?
90% (0.8-1.2)
51
3 BE comparison approaches?
Average Population Individual (also population adn Individual combined)
52
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
53
What 3 things does the comparisons for BE rely on?
criteria to base comparisons confidence inteval for the criteria a predetermiend BE limit
54
What is Cmax influenced by?
rate and extent of absorption
55
What is AUC value influenced by?
extent of absorption
56
Is testing using the nul hypothesis appropriate for BE?
No, mean differences may exist but have no clinical importance
57
Why is the BE range 80-125% for a 90% confidence interval?
b/c range is symmetric; 1.25 = 0.8^-1
58
What is the 90% GMR equation?
90%GMR = 100x e^(difference +/- t(0.05(n1+n2 - 2)xSEdifference)
59
What conditions should BE be demonstrated under for MR products?
fasted and fed studies
60
How are multiple dose MR studies preformed?
under fasting conditions
61
Drugs with serious toxicity within normal dosage range study design?
parallel over crossover
62
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
63
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
64
What is the range for critical dose drugs?
90% CI GMR for AUC between 90-112% Cmax still 80-125%
65
Class I drugs?
high solubility and permeability
66
Class II drugs?
low solubility high permeability
67
Class III drugs?
high solubility low permeability
68
Class IV drugs?
low solubility and permeability
69
What types of drugs are BCS-based biowaivers applicable too?
IR solid oral dosage forms/ suspensions for systemc circulation
70
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
71
at what absolute F is high permeability concluded at?
>=85%
72
What cells can be used to assess and validate permeability?
Caco-2 cells
73
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
74
What is rate limiting for Class I drugs?
dissolution or gastric emptying
75
WHy might F be low for a Class I drug?
first pass metabolism
76
What classes of drugs may biowaicers be probable?
Class I and III
77
What drug class are biowaivers not considered in?
Class IV
78
What are the exceptions where biowaivers are not applied to?
Narrow therapeutic range drugs Drugs for absorption in oral cavity
79
when are 2 dissolution profiles considered similar?
when f2 value is >=50
80
WHen is comparison with an f2 test unnecessary?
when both drugs have 85% or more dissolved in 15 minutes
81
f2 equation?
50x log {[1 + (1/n)Sumt=1^n (Rt-Tt)^2]^-0.5 x100}
82
4 rights?
pt drug time dose
83
how many cells in human body?
30-40 trillion
84
When are cell cycle checkpoints?
G1 and G2
85
Which M phase has a checkpoint?
anaphase; checks spindles
86
what % of human chromosomes code for genes?
10%
87
average chromosome amount of genes and bps?
2500-5000 130 million bps
88
Chromosome structure?
octomer of core histones (H2A, H2B, H3, H4) x2
89
how large is mature mRNA compared to gene size?
about 1/10 in size
90
Nucleotide pairs?
A-T G-C A-U
91
Transcription?
gene-->mRNA
92
Translation?
mRNA--> protein
93
RNA polymerase binding site?
promoters; upstream of genes
94
what occurs to promoters to repress gene transcription?
methylation
95
how many genes in mitochondrial DNA genome?
38
96
4 essential parts of genomic studies?
genetic variations gene expressions gene regulations gene correlations
97
SNP frequency?
1 in 1000 bps to 1 in100-300 bps
98
how many coding SNPs does each gene have approximately
5
99
types f CNVs?
deletion duplication segmental duplication inversion
100
Cystic fibrosis indel?
3 bp deletion in CFTR (F508)
100
Huntingtons INDEL?
triplet repeat of expansions CAG in gene HTT (usually >35)
101
BRCA2 gene INDEL?
6.2kb deletion
102
Structural variation ex?
short arm of chromosome 1
103
hot spots for structural variation?
regions w/ lots of variation
104
Philadelphia chromosome?
balanced translocation of chromosome 9 and 22 leads to ALL and CML
105
What valuable info may SNP genotyping provide?
Drug response Disease suceptibility Treatmnet outcome AE's
106
Tamoxifen CYP enzyme?
2D6
107
P4?
predictive preventative personalized participatory
108
how many exons in DMD gene ?
79
109
Eteplirsen MOA?
exon skipping therapy; skips exon 51, shortened dystrophin formed with ~50% normal function
110
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
111
What was the first FDA approved drug for cancer that targets genetic mutation not a cancer type?
Vitrakvi(Larotrectinib)
112
What is Vitrakvi indicated for?
solid tumors that test positive for NTRK gene fusions
113
Known acquired resistance mutations for Vitrakvi?
G623R, G696A, and F617L
114
Imatinib MOA?
inhibits BCR-ABL TK, proliferation Induce apoptosis in BCR-ABL positive cells
115
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+
116
Palbociclib?
inhibits cyclin-dependant kinases CDK4 and CDK6; prevents cancer cells to pass the R point
117
Palbociclib dosing?
125mg w/ food OD x 21 day 7 days off repeat
118
Tratuzumab subdomain?
IV
119
How does pertuzumab work?
prevents homodimerization of HER2 and heterodimerization of HER2-HER3
120
Combo for metastatic and recurrent HER2+ breast cancer?
Trastuzumab + Pertuzumab +docetaxel
121

PHAR 225 (1 decks)

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