Bioequivalence 1-5 Flashcards
(148 cards)
1
Q
What is a generic? (3)
A
- Copies of brand-name drugs with same active ingredient and for the same intended therapeutic use as innovator product
- Look different from the innovator product
- Cheaper
2
Q
Prior to 1962, drugs were approved for ______ only
A
safety
3
Q
What was developed in 1938 in response to the sulfanilamide tragedy?
A
Federal Food, Drug, and Cosmetic Act
4
Q
What was the thalidomide tragedy? (3)
A
- Used to cure morning sickness in the late 1950s
- Withdrawn from the market in 1961 after being found to be a cause of birth defects
- Birth defects such as: phocomelia, deafness, blindness, disfigurement, cleft palate, etc
5
Q
What were the amendments added in 1962 to the Federal Food, Drug, and Cosmetic Act? (2)
How did generic companies respond?
A
- Added a proof-of-efficacy requirement to new drug approval
- Generics had to meet safety, efficacy and BE criteria
- After 1962, generic companies simply would not spend the time and money doing the clinical trials to get to market
6
Q
What was the 1984 Drug Price Competition and Patent Term Restoration Act? (Hatch-Waxman Act) (3)
A
Established abbreviated new drug application (ANDA) procedure
- Approval of generics of drugs already safe and effective
- Only have to meet pharmaceutical equivalence and bioequivalence
7
Q
Why are generics relevant to us?
What are we expected to know (2)?
A
- Enhancement in availability of generics = decreased costs of healthcare
Pharmacists expected to know:
- What is best for the pt
- What is in the pipeline
8
Q
Two women sued PLIVA Inc. over the labels for metoclopramide, the generic version of Reglan. Reglan did not have a warning about tardive dyskinesia when they were taking it. In 2011, what did the Supreme Court rule?
A
Ruled that makers of generic drugs cannot be sued for failing to warn consumers of the possible side effects of their products if they copy the exact warning on the medicines’ brand-name equivalents
9
Q
Define pharmaceutical equivalent
A
A new drug that, in comparison with another drug, contains identical amounts of the identical medicinal ingredients, in comparable dosage forms, but that does not necessarily contain the same non-medicinal ingredients
10
Q
How does Canada TPD (Health Canada) define bioavailability?
A
Rate and extent of absorption of a drug into the systemic circulation
11
Q
How does Canada TPD (Health Canada) define bioequivalence?
A
High degree of similarity in the bioavailabilities of two pharmaceutical products (of the same active ingredient) from the same molar dose, that is unlikely to produce clinically relevant differences in therapeutic effects, or adverse effects, or both
12
Q
What is the basic assumption of bioequivalence?
A
When a test product is claimed bioequivalent to the reference product it is assumed that the products are therapeutically equivalent and, hence, interchangeable with the reference product
13
Q
What are 2 factors related to dosage form in regards to modifying bioavailability?
A
- Physicochemical properties of drug
- Formulation and manufacturing variables
14
Q
What are 2 factors related to the patient in regards to modifying bioavailability?
A
- Physiological factors
- Interactions with other substances
15
Q
What physicochemical properties of drug can influence bioavailability? (6)
A
- Particle size
- Crystalline structure
- Polymorphic form
- Degree of hydration
- Salt form
- Ester form
16
Q
What are formulation and manufacturing variables that can influence bioavailability? (4)
A
- Amount of disintigrant/lubricant
- Coatings
- Nature of diluent
- Compression force
17
Q
What are some physiological factors that can influence bioavailability? (10)
A
- Differences in mucosal permeability in different GIT regions
- Variations in pH
- Gastric emptying rate
- Intestinal motility
- Perfusion of GIT
- First-pass metabolism
- Age/gender/weight
- Disease
- Stress
- Time of administration
18
Q
What are some potential interactions with other substances that can influence bioavailability? (3)
A
- Food
- Fluid volume
- Other drugs
19
Q
What is relative bioavailability?
A
Extent and rate of bioavailability of drug from two or more different dosage forms given by same route of administration
- Standard used is an approved marketed drug, solution, suspension, or micronized drug
20
Q
Drug Product—————-AUC——————–F
Innovator (IV bolus)——-100———————1
Innovator (Oral bolus)—-50———————-0.5
Generic (Oral bolus)——-40———————___
How would you calculate Frel?
A
50/100 = 0.5 which is how we get innovator oral bolus
40/50 = 0.8 which is Frel for generic (oral bolus)
21
Q
What is rate of bioavailability?
What does it determine?
A
- In essence, represents the apparent absorption rate constant for a drug from the drug product
- Determines time to and height of peak Cp when kd same and absorption complete
22
Q
Tmax and Cmax are indicators of rate of bioavailability. What do they tell us?
A
- Determinants of onset and intensity of effect
- May determine duration of effect
23
Q
Relative optimal bioavailability (ROB) is defined by “true” and “apparent” rate constant. What are those?
A
- Absorption rate constant, ka, from solution is “true” rate constant
- Absorption rate constant from drug product is an “apparent” rate constant
- Liberation and dissolution also occurs
24
Q
On a practical level, bioequivalent studies are required for? (4)
A
- Any new generic product
- An innovator manufacturer to show product to be marketed is bioequivalent with the formulation used in pivotal clinical trials
- If innovator manufacturer changes the formulation of a drug already on the market or introduces additional dosage strengths
- When considering new route of administration
25
Waiver of bioequivalence is allowed in certain cases. Such as? (5)
1. Solution intended for IV use
2. Typically applied for local use
3. Oral dosage form not intended to be absorbed
4. Administered by inhalation
5. Solution, elixir, syrup, tincture, etc. form of an approved product and contains no inactive ingredient known to affect bioavalability
26
The US-FDA and CAN-TPD has a descending order of preference when it comes to type of bioequivalence studies. What is that order (6)
1. Pharmacokinetic study (PK-BE)
2. Pharmacodynamic study (PD-BE)
3. Comparative Clinical Study
4. In vitro study
- Dissolution study
- Biopharmaceutics Classification System Biowaivers
27
When is an acute pharmacodynamic study used?
What enpoint(s) does it use?
Example?
1. Used when PK approach not possible (i.e., locally acting drug product)
2. Uses a pharmacological or clinical endpoint
e.g., Forced expiratory volume for inhaled bronchodilators
28
What are the PD parameters used for an acute pharmacodynamic study? (3)
1. AUC of the PD effect vs. time curve
2. Peak PD effect
3. Time for peak PD effect
29
What do acute pharmacodynamic studies require? (4)
1. Must be validated (accurate, sensitive, reproducible)
2. Requires demonstration of a dose-response curve
3. Doses should produce a range of response values
4. Instrumental measurements should be made under double-blind conditions
30
Many PD tests are difficult to quantify. Why? (2)
1. Placebo effects --> increase sample size
2. PD variability is large --> increase sample size
31
What are the disadvantages of clinical studies (of bioequivalence)? (2)
1. Least accurate, least sensitive, least reproductive
2. Considered only when analytical and PD not available
32
When are clinical studies (of bioequivalence) used?
Example?
Used when neither PK nor PD approach possible
e.g., was used to establish bioequivalence for topical antifungal drug products (e.g., ketoconazole)
33
How are clinical studies (of bioequivalence) done?
Uses a controlled clinical blind or double blind study --> BE established through evaluation of clinical response
34
How are pharmacokinetic studies done? (What do they use?) (2)
1. Uses PK measures to determine rate/extent of drug release from product and absorption into systemic circulation
2. Uses "Exposure Concept of Bioequivalence" to reflect clinically important differences in T vs. R
35
What 3 things make up Exposure Concept of Bioequivalence?
1. Total exposure (AUC0-->∞ for single dose; AUC0-->𝜏 for multiple dose)
2. Peak exposure (Cmax)
3. Early exposure (partial AUC to peak time)
36
What are the 4 ethics approvals needed for Good Clinical Practice (bioequivalence studies)
1. Institutional Human Ethics Review
2. Informed consent
3. Pre-study physical exam and medical history
4. Post-study physical exam
37
When doing a BE study, subjects should be selected to reduce: (2)
1. Risk to study subjects
2. Inter- and intra- subject variability
38
When doing a BE study, normal healthy volunteers (male and/or females) are chosen. What are some of the requirements/what is checked? (6)
1. Age (18-55yr)
2. BMI within 18.5 and 30
3. Medical examination, history, routine tests of liver, kidney, and hematological functions
4. Alcohol and drug abuse
5. An ECG if the drug is known to affect ECG
6. Not pregnant, lactating, or likely to become pregnant
39
A BE study design considers the 3 fundamental statistical concepts of study design. Which are?
1. Randomization
2. Replication
3. Error control
40
What is study randomization?
Allot treatments to subjects without selection bias
41
What is study replication?
Treatment applied to more than one experimental unit
- Number of replicates depends on degree of differences to be detected and inherent variability of the data
42
What is study error control?
Goal is to reduce sources of experimental error
43
What is the typical Single Oral Dose (SOD) design? (4)
1. 2-product
2. 2-period
3. 2-sequence
4. Crossover
44
What are the characteristics of crossover study design? (3)
1. Crossover diminishes intersubject variation (not product dependent), and allows examination of intrasubject variation (product dependent)
2. Replicated cross-over designs - the formulations are tested more than once in the same subjects
3. More periods and sequences - more than two formulations, or different study conditions
45
Parallel group study design does not allow for what?
A within-subject comparison (so need increased N)
46
Only consider parallel group study design if: (2)
1. Drug has very long half-life
2. Some depot formulations
47
The number of subjects with desired power and significance level depends on: (4)
1. Mean difference between T and R (typically +/-20%)
2. Intra-subject variance
3. Power (typically 0.8)
4. Type I error rate of 5%
48
In a study, the minimum number of subjects is __
Accounting for what 2 things?
12
- Accounting for drop-outs
- Accounting for outliers
49
What is blinding (study design)? (3)
1. Study subjects blinded to particular product
2. Person checking for adverse reactions blinded
3. Person analyzing samples blinded
50
Food and fluid administration has to be controlled when conducting a study. What are 3 things to make it standardized?
1. Fast 8h, water consumed up to 1h before drug administration; dose at same time of day
2. Dose taken with standard volume of water (150-250ml) at a standard temperature
3. Water and food 1 and 4h after, respectively
51
Serial blood samples are taken at intervals to define Cp vs. time curve.
How many samples?
How many half-lives?
1. Minimum of 12 samples should be collected per subject per dose
2. Sample for at least 3 half-lives
52
Describe the conduct of a study? (SOD type study I guess) (6)
1. Each subject takes T or R with 150-250ml water
2. Serial blood samples are taken at intervals to define Cp vs time curve
3. Plasma collected and frozen
4. Allow sufficient washout (>10 half-lives) and then next formulation taken
5. Monitor and record adverse effects
6. Validated assay determines drug concentration
53
What are the advantages of multiple-dose administration studies? (5)
1. For patients in whom it would be unethical to ds/c treatment
2. Do not need to extrapolate to get total AUC
3. More closely reflects clinical use of drug
4. Allows Cp measured at therapeutic levels
5. Can detect nonlinear PK
54
What are the disadvantages of multiple-dose administration studies? (3)
1. More time and more difficult and costly
2. Issues with compliance control
3. Increased potential for AEs
55
What are the 3 parameters that characterize rate and extent of bioavailability in a single dose study?
1. AUC 0-->∞
2. Cmax
3. Tmax
56
What are the 2 parameters that characterize rate and extent of bioavailability in a multiple dose study?
1. AUC𝜏n -->𝜏n+1
2. % fluctuation
57
What is the equation for % fluctuation?
% Fluctuation = ((Cssmax - Cssmin)/Cssmin) x 100
58
What 2 things are are done in PK and Statistical Assessment?
1. Cp vs. time curve constructed
2. Calculate important PK parameters for both T and R and report summary of the estimates including means and SD
59
Do T and R products differ within a predefined level of statistical significance? (3)
1. Early 70s BE based on mean data
2. Mean AUC or Cmax of T had to be within +/-20% of R
3. The 20% arbitrary --> physicians 'felt' that a 20% change in dose would not result in significant differences in clinical response
60
One of the current statistical guidelines for BE is logarithmic transformation of BE metrics.
What is this? (2)
1. In BE, examine difference in means (DIM) of Cmax and AUC between T and R
2. For Cmax and AUC their values must be logarithmically transformed before statistical analysis
61
What is the equation for Difference in Means (DIM)?
Diff = ln(µT/µR) = ln(µT) - ln(µR)
62
Another one of the current statistical guidelines for BE is the confidence interval approach. What is this? (3)
1. Two one-sided tests: if the bioavailability of test formulation is too low or high
2. 90% confidence interval for the ratio of means 0.8-1.20
3. When log-transformed data are used, the 90% confidence interval is set at 80-125%
63
For BE, drug products must be equivalent with respect to rate and extent of drug absorption. The predominant issues, then, are: (2)
1. PK criteria:
- BE measures expressed in systemic exposure measures
- Assume these measures relate to safety and efficacy outcomes
2. Statistical criteria:
- What is the most appropriate method of statistical analysis of the data
64
What is 'average BE'? (2)
Special case of individual BE where there is no subject-by-formulation interaction and T and R variances are equal
- Focuses only on comparison of population averages of a BE measure not on its variance
65
What are the 3 approaches for BE comparisons?
1. Population BE
2. Individual BE
3. Population and Individual BE
66
What is population BE? (2)
1. Relies on population estimates
2. Population BE approach determines total variability of the BE measure in population
67
What is individual BE? (2)
1. Considers the individual
2. Individual BE assesses within-subject variability of T and R products and subject-by-formulation interaction
68
The statistical model is an analysis based on parametric statistics of the logarithm of the metrics (AUC, Cmax). What 3 things does it assume
1. Normality - log normal distribution of random variables
2. Independent - random variables are independent
3. Homoscedasticity - variance of dependent variable is constant and does not change with independent variable (formulation, subject, period)
69
BE studies: How do we select the reference product? (2+3)
1. Traditionally the innovator product
2. Today, standards can also be:
- Aqueous true solution of drug
- Aqueous solubilized system of the drug
- Aqueous suspension of micronized drug
70
What is 'exposure concept of BE'? (2)
1. Cmax and AUC considered clinically relevant measures
2. Represent peak exposure and total exposure, respectively
71
Comparisons for BE rely on: (3)
1. A criterion (to base comparisons)
2. A Confidence Interval for the criterion (provides the "statistics" to determine whether comparisons are different or not)
3. A predetermined BE limit (to decide whether the relative BA is acceptable)
72
What are the advantages of single oral dose studies? (3)
1. No disease problems (BA assumes no physiological changes during study)
2. Control of potential confounding factors (diet, fluid volume intake, etc.)
3. No polypharmacy (no drug interactions)
73
What is the disadvantage of single oral dose studies?
Cannot do PD study (since healthy)
74
Estimates of the following PK parameters should be tabulated for each subject-formulation combination: (8 - only 1, 4, and 8 important for us)
1. AUC(T)
2. AUC(I)
3. AUC(T)/AUC(I)
4. Cmax
5. tmax
6. λ (terminal disposition rate constant)
7. t1/2
Where the time to onset of action is important, the following parameter should also be reported:
8. The area under the curve to tmax of the reference product, calculated for each study subject (AUC Reftmax)
75
The analysis of any comparative bioavailability study should have
the following sections: (4)
a) A randomization scheme for the design, where all subjects
randomized into the study are included and identified by code,
sequence, and dates of the dosing periods for both test and
reference formulations.
b) A summary of drug concentrations (graphic and quantitative)
at each sampling time for each subject for both test and
reference formulations.
c) A summary of the estimates of the parameters for both test
and reference formulations, including the means, standard
deviations, and CVs.
d) A formal statistical analysis of the relevant parameters with
comparisons of the test formulations to the reference
formulations.
76
To establish BE, compare the test and reference product metrics, Cmax and AUC0-->∞
What makes up the Cmax value? (3)
1. Influenced by rate and extent of absorption
2. Measure of “peak exposure”
3. Metric recommended to evaluate rate of absorption
77
To establish BE, compare the test and reference product metrics, Cmax and AUC0-->∞
What makes up the AUC value? (3)
1. Influenced by extent of absorption
2. Measure of “total exposure”
3. Metric recommended to evaluate extent of absorption
78
Analysis of Variance (ANOVA) is used when?
ANOVA can deal with several sources of variability --> Between Subject Variability (BSV) and Within Subject Variability (WSV)
79
What are the sources of variance in ANOVA model in relation to BE (2)?
1. BSV (between subject variability)
- Variability associated with product, period, sequence, subject
2. Residual variance
- Residual or error mean square in ANOVA
- Estimates the WSV
80
Residual variance contains several variance components. What are they? (5)
1. WSV in PK (day to day variation in ADME)
2. Analytical variability
3. Within product variability (tablet to tablet)
4. Subject by formulation interaction
5. Unexplained random variation
81
True or False? ANOVA test of simple null hypothesis is appropriate?
False - inappropriate
82
CI test is used as BE test to evaluate what?
Whether the mean amount of drug absorbed using test is close to that of reference
83
CI calculated from ___
WSV (within subject variance)
- smaller the variability, the narrower the CI
84
Confidence Interval Approach: What is Bioequivalence Range? (4)
1. The standard equivalence criterion (i.e. the BE limits) is 80-125% for the 90% CI of the ratio of the geometric means
- Range is symmetric as 1.25 = 0.8-1
2. The BE limits
- Physicians suggested difference of up to 20% in Cmax or AUC between two formul’ns has no clinical significance
3. The 90%CI must fall entirely within the BE limits of 80-125%
4. Setting BE limits at 80-125% is a “one size fits all” approach
85
What are the basic steps of statistical analysis for BE determination? (4)
1. BE metrics are natural logarithmically transformed and subjected to ANOVA analysis
2. The mean difference between the transformed data for each metric are then calculated (geometric mean ratio)
3. Standard error of the difference in the means is calculated
4. High and low bounds of the CI about the mean difference of the transformed data is calculated
86
How to calculate the 90%CI?
BE is concluded if 90%CI for the AUC and Cmax geometric mean ratios of the two formulations lie in the BE range (80-125%)
87
90%CI = 100 x e^(Difference +/- t0.05,(n1+n2-2) x SEDifference)
This equation is given on the exam, but you should know what's going on here.
Where: Difference is the difference in the natural log of means
between T and R; t0.05 is the critical value of t-stat with 𝜶 = 0.05
in one tail; n1+n2-2 is the degree of freedom where n1 and n2
are the number of subjects in the sequence TR and RT,
respectively; SEDifference is the standard error of the difference.
88
When is BE declared? (2)
1. BE declared if the calculated 90% CI around the ratio of the geometric means falls completely within the predefined BE limits of 0.8-1.25
2. Ensures consumer safety since probability of an erroneous acceptance of BE does not exceed the preset level of significance (0.05)
89
The reported results of a BE study should include: (4)
1. Arithmetic means and CVs (across subjects) for each product;
2. Testing and estimates for fixed and random effects;
3. AUCT and Cmax ratios of geometric means for test versus reference products;
4. The appropriate confidence interval about the parameter being analyzed.
90
In summary, TPD standards for BE for uncomplicated drugs requires the following data for the two products: (3, really 6 though)
1. AUCT, AUCI
2. Cmax, Tmax
3. k, half-life
91
In summary, TPD standards for BE for uncomplicated drugs should be designed how? (3)
1. SOD crossover design in fasted subjects
2. 90%CI around the ratio of the geometric means for lnAUClast of the T and R should be within BE limits of 80-125%
3. Ratio of the geometric means of Cmax for T and R should be between BE limits of 80-125%
92
Why do modified release (MR) drugs require different regulations? (2)
1. Increased likelihood that increased between-subject variability in BA will occur, including dose-dumping
2. Increased risk of adverse effects depending upon the site of release, absorption, or both
93
Under what conditions do MR drugs' need to demonstrate bioequivalence?
Both fasted and fed conditions
94
How is a single oral dose MR study performed? (4)
1. Comparison between single dose of generic MR and innovator's conventional formulation generic MR is intended to replace
2. Healthy volunteers
3. Fasted and Fed studies
4. Four-period crossover trial (replicate design)
95
What are the BE standards required for single oral dose MR studies? (2)
1. 90%CI around the GMR for AUC of T and R should be within the BE limits of 80-125% in fasted and fed states
2. The GMR of Cmax for T and R formulations should be within 80-125% in fed and fasted states (No 90%CI required here)
96
How is a multiple oral dose MR study performed? (2)
1. Steady-state studies are not generally required
2. Performed under fasting conditions unless safety of subjects requires that drug product be administered with a meal
97
What are the BE requirements for a multiple oral dose MR study? (3)
1. 90%CI around the GMR for AUC𝜏 of T and R should be within BE limits of 80-125%
2. GMR of Cmax at SS for T and R should be within 80-125% (no 90%CI required)
3. GMR of Cmin at SS for T and R should not be less than 80%
98
Modified-release products with multiphasic plasma concentration profiles - partial AUC (pAUC). The specific pAUC time intervals to be considered will be based on clinical data showing the therapeutic relevance of the particular time interval, for example? (4)
1. Early onset
2. Maintenance
3. Dose clearance
4. Fasted versus fed state
99
When doing food-effect BA and fed BE studies, what types of foods are best to use?
Use high calorie and high fat meals
- Has greatest effect on GIT physiology
100
Explain how food-effect BA and fed BE studies are designed (5)
1. BE first demonstrated in a SOD study under fasting conditions
2. Randomized, balanced, single-dose, two-treatment (T and R following a test meal), two-period, two-sequence crossover for both IT and MR drug products
3. Use highest strength of drug product
4. Following 10h fast, administer drug 30 mins after start of meal with 240mL of water
5. No food allowed for 4 hours post dose
101
How are drugs with serious toxicity within the normal dose range studied? (6)
1. Drugs with serious toxicity - study in patients.
2. Study bioavailability at steady‐state.
3. The test drug product replace the reference drug product for at least five half‐lives before sampling.
4. Standardization of the study conditions is essential, particularly with respect to the time of day of drug administration and posture of the subject.
5. Parallel rather than cross‐over design.
6. Same standards for multiple‐dose studies on modified‐release dosage forms.
102
How are drugs that exhibit non-linear PK studied? (3)
1. For drugs with greater than proportional increases in AUC with increasing dose, the comparative bioavailability study should be conducted on at least the highest strength.
2. For drugs with saturable absorption and resulting in less than proportional increases in AUC with increasing dose, the comparative bioavailability study should be conducted on at least the lowest strength (single dose unit).
3. For drugs with limited solubility of the medicinal ingredient and resulting in less than proportional increases in AUC with increasing dose, the comparative bioavailability studies should be conducted on at least the lowest strength (single dose unit) in the fasted state and the highest strength in both the fasted and fed states.
103
TPD indicates drugs with effective half-lives >24h require BE guideline modification. These drugs have same BE criteria except for the following: (2+3)
1. The AUC0-72 will be used as the comparison parameter
2. Require very long washout periods so crossover maybe replaced with following:
- Parallel group designs
- Steady state studies in volunteers or patients
- Use of stable isotopes
104
What additional requirements are needed (on top of standard requirements) for drugs with an important time of onset of effect or rate of absorption? (e.g., analgesic for rapid relief of pain)
The relative mean area under the curve to the time of the maximum concentration of the reference product (AUC Reftmax) of the test to the reference formulation should be within 80-125% inclusive
105
What are the TPD critical dose drugs? (9)
1. Cyclosporine
2. Digoxin
3. Flecainide
4. Lithium
5. Phenytoin
6. Sirolimus
7. Tacrolimus
8. Theophylline
9. Warfarin
106
Health Canada defines crtitical dose drugs as?
“drugs where comparatively small differences in dose or concentration lead to dose‐ and concentration‐dependent serious therapeutic failures and/or serious adverse drug reactions which may be persistent, irreversible, slowly reversible, or life threatening, which could result in inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, or death. Adverse reactions that require significant medical intervention to prevent one of these outcomes are also considered to be serious.”
107
What are the BE requirements of critical dose drugs? (4)
1. 90% CI around the GMR for AUC of the T and R formulations should be within the BE limits of 90-112%
2. 90%CI around the GMR for Cmax for the T and R formulations should be within the BE limits of 80-125%
3. Must be met in fasted and fed states
4. Steady‐state studies are not required for critical dose drugs unless warranted by exceptional circumstances.
108
Critical dose drugs may need to conduct studies in patients who are already receiving the drug as part of their treatment, rather than in healthy subjects. How are these drugs studied? (4)
1. Study bioavailability during a dose interval at steady‐state.
2. The test drug product replaces the reference drug product over a period of at least five half‐lives before sampling.
3. Parallel rather than cross‐over design.
4. If a steady‐state study is required, the 90% confidence interval of the relative mean Cmin of the test to reference product should also be within 80.0% ‐ 125.0% inclusive.
109
How are combination products studied?
For all combination products, the PK parameters to be reported and assessed are those which would normally be required of each drug if it were in the formulation as a single entity
110
What is a highly variable drug?
When within-subject coefficient of variation (CV) of the applicable AUC for the reference product is greater than 30.0%
111
Highly variable drug products need to demonstrate that the CV (coefficient of variation) estimates are reliable. How? (2)
1. Replicate design with the reference product (R) administered at least twice
2. The test product (T) should be adminstered either once in a 3-period design (RTR, TRR, RRT) or twice in a 4-period design (TRTR, RTRT)
112
The 90%CI of the relative mean AUC of the test to reference product (of highly variable drug products) should be within the following limits:
1. If CV ≤ 30.0%
2. If 30.0% < CV ≤ 57.40%
3. If CV > 57.40%
1. 80.0-125.0%
2. [exp(-0.76sWR) x 100.0%] - [exp(0.76sWR) x 100.0%]
3. 66.7-150.0%
The relative mean AUC of the test to reference product should be within 80.0% and 125.0% inclusive
113
What is an alternative study design for highly variable drug products?
1. As an alternative to the use of expanded bioequivalence limits for HVDPs, the variability in the drug’s pharmacokinetics may be addressed through the study design.
2. E.g., pre‐screened sub‐population such as slow metabolizers, in which the variability may be lower.
3. This type of flexibility in study design does not require the application of special bioequivalence standards
114
How are drugs with measurable endogenous levels studied? (4)
1. In cross‐over studies, test and reference products should be administered at the same time of day, to reduce the potential contribution of diurnal variation.
2. Drug doses should be high enough to differentiate exogenous levels from endogenous levels.
3. Baseline‐corrected plasma concentrations should be used in statistical analysis.
- Subtract the estimated endogenous baseline concentration from each post‐dose concentration.
- Individual baseline levels be calculated in each period prior to dosing - fluctuations in endogenous concentrations.
- Negative concentrations should be set to zero.
4. Alternate approaches to dealing with endogenous levels may be acceptable.
115
How are pharmacodynamic studies done? (4)
1. Drugs for which pharmacodynamic studies are appropriate alternatives to comparative bioavailability studies of oral dosage formulations.
2. Justify why other methods are unsuitable.
3. Choose study endpoints and schedule.
- Measures of the magnitude, onset, and duration of response.
- AUC = cumulative pharmacodynamic response
- Cmax = peak response.
4. Use acceptance criteria similar to those defined for comparative bioavailability studies.
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What is the biopharmaceutics classification system? (2)
1. Scientific framework for classifying drug substances based on aqueous solubility and intestinal permeability
2. Predicts in vivo PK performance of drug products
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The biopharmaceutics classification system considers the factors influencing rate and extent of absorption, such as? (3)
1. Aqueous solubility
2. Dissolution rate
3. Intestinal permeability
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What are the 3 steps of drug absorption?
Disintegration --> Dissolution --> Absorption
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The biopharmaceutics classification system (BCS) categorizes drug substances into one of four BCS classes.
What is Class I in terms of solubility and permeability?
What is the extent of absorption?
High solubility; high permeability
Extent of absorption = very good
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The biopharmaceutics classification system (BCS) categorizes drug substances into one of four BCS classes.
What is Class II in terms of solubility and permeability?
What is the extent of absorption?
Low solubility; high permeability
Extent of absorption = dissolution rate-limited
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The biopharmaceutics classification system (BCS) categorizes drug substances into one of four BCS classes.
What is Class III in terms of solubility and permeability?
What is the extent of absorption?
High solubility; low permeability
Extent of absorption = permeability-rate limited
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The biopharmaceutics classification system (BCS) categorizes drug substances into one of four BCS classes.
What is Class IV in terms of solubility and permeability?
What is the extent of absorption?
Low solubility; low permeability
Extent of absorption = very poor
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BCS-based biowaivers may be used to substantiate in vivo bioequivalence. Such as? (3)
1. Comparsion between products used during clinical development through commercialization
2. Post-approval changes in formulation
3. Generic drug products
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The BCS-based biowaiver is only applicable to which types of medications?
Immediate release, solid orally administered dosage forms or suspensions designed to deliver drug to the systemic circulation
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BCS solubility classification is based on what?
Highest dose strength of the IR product
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How is BCS solubility classification performed? (4)
1. Highly soluble when completely soluble in ≤ 250 mL aqueous media over pH 1.2-6.8 at 37°C
2. At least 3 pHs within this range, including buffers at pH 1.2, 4.5, and 6.8
3. Solubility at the pH of lowest solubility of the drug substance should be evaluated if it is within the specified pH range
4. The lowest measured solubility over the pH range of 1.2-6.8 will be used to classify the drug substance
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BCS - high permeability can be concluded when the absolute bioavailability is ≥__%
85%
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How is BCS permeability classification performed? (4)
1. Human in vivo data derived from published literature may be acceptable – need to evaluate the quality of the results.
2. Permeability can be also assessed by validated and standardized in vitro methods using Caco-2 cells.
3. The results from Caco-2 permeability assays should be discussed in the context of available data on human pharmacokinetics.
4. If high permeability is inferred by means of an in vitro cell system, permeability independent of active transport should be proven.
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Explain how Caco-2 permeability assay is performed (3)
1. Insert is soaked in a chamber. This insert, at the bottom, has a semi-permeable membrane (allows molecules to cross the bottom part of the insert quite freely).
2. If you culture Caco-2 at the bottom of the insert on top of the permeable membrane, they will cover the whole surface. Leave no gap between the cells. If a molecule wants to go from one side of the chamber to the other side - the only way is to diffuse across this cell layer. That is what makes these cells so special, and a good analogue for intestinal cells.
3. Put your test drug in one side of the chamber. Put another well known drug as an internal reference.
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When doing permeability classification, what is the reference drug? Why?
Metoprolol. Fraction absorbed is 85%, which is right on the boundary of highly permeable or not, since >85% is highly permeable.
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For BCS classes I through IV, should know whether or not biowaiver is likely or not.
Class I - biowaiver probable
Class II - biowaiver unlikely
Class III - biowaiver possible
Class IV - biowaiver not considered
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What is F of a class I drug?
What is the rate-limiting step?
- F may be low due to first-pass metabolism
- Rate limiting step is dissolution or gastric emptying
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What are 2 situations in which a biowaiver may be applicable?
1. When the drug substance(s) in test and reference products are identical
2. If test and reference products containing different salts provided that both belong to BCS class I
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When are biowaivers not applicable?
When the test product contains a different ester, ether, isomer, mixture of isomers, complex or derivative of a drug substance
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Are pro-drugs eligible for a biowaiver?
May be considered when absorbed as the pro-drug
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What are 2 exceptions to biowaiver application? (aka biowaiver not applied to these)
1. Narrow therapeutic range drugs
2. Drugs for absorption in oral cavity
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Excipients are another consideration that must be made when requesting biowaiver. Why? (2)
1. Sometimes influences rate and extent of absorption
2. Where excipient differences exist, they should be assessed for their potential to affect in vivo absorption
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Comparative in vitro dissolution tests should be conducted for BCS based biowaiver.
What are the apparatusses used?
Paddle or basket
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Comparative in vitro dissolution tests should be conducted for BCS based biowaiver.
What is the volume of dissolution medium?
900mL or less (it is recommended to use the volume selected for the quality control (QC) test)
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Comparative in vitro dissolution tests should be conducted for BCS based biowaiver.
What is the temperature of the dissolution medium?
37 +/- 1°C
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Comparative in vitro dissolution tests should be conducted for BCS based biowaiver.
What is the agitation speed?
1. Paddle apparatus = 50 rpm
2. Basket apparatus = 100 rpm
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Comparative in vitro dissolution tests should be conducted for BCS based biowaiver.
What are the 3 buffer pHs?
1.2, 4.5, and 6.8
Additional investigation may be required at the pH of minimum solubility (if different from the buffers above)
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To qualify for BCS Class I drug substances, both the test product and reference product should display either very rapid or rapid dissolution.
What are these defined as?
1. Very rapid dissolution = ≥ 85% for the mean percent dissolved in ≤ 15 minutes
2. Rapid dissolution = ≥ 85% for the mean percent dissolved in ≤ 30 minutes
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Comparative dissolution studies should have similar in vitro dissolution characteristics under all of the defined conditions. But in cases where they differ, what needs to be demonstrated?
In cases where one product has rapid dissolution and the other has very rapid dissolution, similarity of the profiles should be demonstrated
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How is comparison of dissolution profiles done?
The similarity factor, f2 should be estimated using the f2 formula.
This is a way of comparing 2 dissolution profiles by taking into consideration every data point
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Two dissolution profiles are considered similar when the f2 value is ≥__
50
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When is an f2 test unnecessary?
When both test and reference products demonstrate that ≥85% of the labelled amount of the drug is dissolved in 15 minutes - dissolution profiles are considered similar
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In summary, what are dissolution studies and what are they used for/what do they tell us? (5)
1. Critical study in drug product development
2. Innovator and generic companies perform these
3. Used to assess batch-to-batch quality
4. Provides quality assurance
5. Assess need for further BE studies relative to minor post approval changes
