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PHAR 225 > Bioequivalence > Flashcards

Bioequivalence Flashcards

1
Q

When did experts realize the importance of bioanalytical assays?

A

In the mid 1950s (increased recognition that different products with the same amount of active ingredients may have different therapeutic responses)

This is due to manufacturing technique, exipients, environmental conditions, etc.

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2
Q

What was the impetus for the formation of the early form of the FDA?

A

Sale of a toxic concoction (sulfanilamide+diethylene glycol) that killed 100 people was marketed to be healthy

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3
Q

What happened with the Thalidomide tragedy?

A

It was used to cure morning sickness in late 1950s, but withdrawn after found to be a cause of birth defects

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4
Q

What was the effect of the 1962 amendments to the FDA?

A

Added a proof-of-efficacy requirement to new drug approval (new generics had to meet safety, efficacy, and BE criteria)

This effectively halted generic drug industry

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5
Q

What was the effect of the 1984 Drug Price Competition and Patent Term Restoration Act?

A

Established the ANDA (abbreviated new drug application)

Approval of generics for already proven drugs only need to meet pharmaceutical equivalence and BE (reduced requirements to stimulate generic drug industry)

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6
Q

Are generic drug manufacturers liable for any side effects beyond the side effects for the brand name product?

A

No, as long as the generic drug manufacturer lists all of the warnings from the brand name manufacturer

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7
Q

What is the definition of pharmaceutical equivalents?

A

A new drug that, in comparison with another drug, contains identical amounts of the identical medicinal ingredients

Does not necessarily contain the same exipients (similar extent and rate of absorption)

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8
Q

What is the FDA definition of bioavailability?

A

It is the rate (Tmax, ka) and extent (AUC) to which the active ingredient or moiety is absorbed from a drug product and becomes available at the site of action.

Purposesly avoids system circulation (distribution, no need to measure drug concentrations in time intervals)

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9
Q

What is the Canadian definition of bioavailability?

A

It is the rate (Tmax, ka) and extent (AUC) of absorption of a drug into the systemic circulation

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10
Q

What is the FDA definition of bioequivalence?

A

The absence of a significant difference in rate (Tmax, ka) and extent (AUC) to which active ingredient becomes available at site of drug action when administered at the same molar dose

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11
Q

What is the Canadian definition of bioequivalence?

A

High degree of similarities in the bioavailabilities of two pharmaceutical products from the same molar dose which is unlikely to produce clinically relevent differences in therapeutic effects

*In Canada, we have a more stringent burden of proof on manufacturers to show bioequivalence

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12
Q

What is the basic assumption of bioequivalence?

A

When a test product is claimed to be bioequivalent it is assumed that the products are therapeutically equivalent and interchangable

Good response to patients questioning the efficacy of generic products

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13
Q

What factors modify bioavailability?

A
  • Physicochemical properties of drug
  • Formulation and manufacturing variables
  • Physiological factors (differences in GIT regions, variations in pH, GI motility, first pass metabolism)
  • Interactions with other substances
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14
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

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15
Q

What is rate of bioavailability?

A

Represents the apparent absorption rate constant for drug from drug product

Determines time to and height of peak Cp when kd same and absorption complete (Tmax and Cmax are indicators of rate of F)

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16
Q

What is relative optimal bioavailability?

A

Absorption rate constant, ka from solution (disintegration and dissolution are skipped) is true rate constant

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17
Q

What types of activity require BE studies be performed?

A
  • Any new generic product
  • An innovator manufacturer to show product to be marketed is BE with the formulation used in clinical trials
  • Following changes to formulation of a drug already on the market
  • When considering new route of administration
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18
Q

What types of drug formulations do not need in-vivo bioanalysis studies?

A

Class I BCS drugs

  • Solution intended for IV use
  • Topically applied for local use
  • Oral dosage form not intended to be absorbed (Cp is not a good indicator for drug affect)
  • Administered by inhalation
  • Solution, elixir, syrup, tincture, etc. (contains no inactive ingredient known to affect BA)
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19
Q

What are the different types of bioequivalence studies performed by FDA and Health Canada in descending order of preference?

A
  • Pharmacokinetic study (PK-BE)
  • Pharmacodynamic study (PD-BE)
  • Comparative Clinical Study
  • In Vitro Study (need BCS waivers)
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20
Q

When are acute pharmacodynamic studies (PK-BE) performed to show bioequivalency?

A

Used when PK approach not possible (locally acting drug product)

Uses a pharmacological or clinical endpoint

ex. FEV for inhaled bronchodilators

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21
Q

What are the characteristics of acute pharmacodynamic studies?

A
  • Must be validated (accurate, sensitive, reproducible)
  • Requires demonstration of a dose-response curve
  • Many PD tests difficult to quantify
  • Placebo effects = larger sample size
  • PD variability = larger sample size
  • Doeses should produce a range of response values
  • Instrument measurements should be made under double-blind conditions
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22
Q

When are comparative clinical studies performed to show bioequivalence?

A

Used when PK or PD approach possible

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23
Q

How do comparative clinical studies show bioequivalency?

A

Uses a controlled clinical blind or double blind study (BE established through evaluation of clinical response)

Ex. clinical studies showed bioequivalence for antifungal products (Ketoconazole)

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24
Q

What are some disadvantages of using clinical studies to show bioequivalence?

A
  • Least accurate, last sensitive, least reproductive
  • Considered only when analytical and PD not available
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25
Q

How do pharmacokinetic studies (PK-BE) show bioequivalency?

A

Uses PK measures to determine rate/extent of drug release from product and absorption into systemic circulation

ex. Compare AUC, Cmax, and early exposure (partial AUC to peak) to show bioequivalence

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26
Q

What are some major components of an ethics approval?

A
  • Institutional Human Ethics Review
  • Informed consent
  • Pre-study physical exam and medical history
  • Post-study physical exam and medical history
  • Post-study physical exam
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27
Q

What are some considerations for selecting subjects?

A
  • Minimize risk to study subjects
  • Minimize inter- and intra- subject variable
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28
Q

What are some common subjectg criteria for bioequivalence studies?

A

Normal, healthy volunteers (male or female)
- Age (18-55yo)
- BMI (18.5-30)
- Routine medical examination and thorough histroy
- Alcohol and drug abuse
- An ECG (especially if drug is QTc prolonging)
- Not pregnant, lactating, or likely to become pregnant

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29
Q

When are bioequivalence studies started in patients already using the drug?

A

Usually done when it is unethical to administer said drug to healthy volunteers

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30
Q

What are the three fundamental statistical concepts of study design?

A
  • Randomization
  • Replication
  • Error control (minimize experimental error)
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31
Q

What is the most common bioequivalency study design?

A

Single Oral Dose (SOD) Design

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32
Q

Review slide 41 for a brief description of the typical Single Oral Dose (SOD) Design

A
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33
Q

How does the Single Oral DoseI (SOD) study design work?

A
  • PK data from a patient is collected after one dose of Product A (reference) or B (test)
  • Following a washout period, the subjects are switched to a different treatment group
  • PK data from patients is collected again after a single dose of Product B (test) or A (reference)

see slide 41

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34
Q

What are the advantages of crossover study designs?

A

Diminish intersubject variation
More than two formulations and different study conditions can be studied

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35
Q

What are the limitations of parallel group study design for bioequivalency studies?

A

Does not allow a within-subject comparison (each individual only takes one drug, not both like crossover design)

Need to increase sample size to acheive same power as cross-over designs

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36
Q

When are parallel group designs considered for bioequivalence studies?

A

Only considered if:
- Drug has a very long half-life
- Some depot formulations

Parallel study designs are used in these situations because the washout periods are too long and it is unpractival to continue the study after the washout period (subjects have grown and changed since)

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37
Q

What is the significance of the number of subjects?

A

The number of subjects with desired power and significance level depends on the following:
- Mean difference between test and reference (typically +/- 20%)
- Intra-subject variance
- Power (usually 0.8)
- Type I error rate of 5%

Minimum number of subjects for a BE study is 12 (accounting for drop-outs and outliers)

38
Q

How can study conditions be standardized?

A
  • Posture, exercise, diet, smoking, alcohol use, other drugs
  • Minimize P450 interactions
  • Blinding (triple blinding is preferred)
  • Control food and fluid administration (150-250mL 1 hour after admin, food after 4 hours)
39
Q

Describe how a general PK-BE study is conducted?

A
  1. Each subject takes T or R with 150-250mL of water
  2. Serial blood samples taken to define Cp vs time curve (minimum 12 samples, more data points are positioned to determine accurate Cmax and elimination rate constant (k), sample for at least 3 half-lives)
  3. Plasma collected and frozen for future analysis
  4. Allow minimum 10 half-life washout period before subsequent testing
  5. Monitor and record adverse effects
  6. Validated assay determines drug concentration
40
Q

What are some reasons to conduct multple dose bioequivalence study designs?

A
  • For patients in whom it would be unethical to stop treatment
  • Do not need to extrapolate to get total AUC
  • More closely reflects clinical use of drug
  • Allows Cp measured at therapeutic levels
  • Can detect non-linear PK
41
Q

What are some disadvantages associated with multiple dose bioequivalence study designs?

A
  • More time, difficulty, and cost
  • Issues with compliance control
  • Increased potential for adverse effects
42
Q

For single dose BE designs, what parameters are used to characterize the rate and extent of bioavailability?

A

AUC, Cmax, Tmax

43
Q

For multiple dose BE designs, what parameters are used to characterize the rate and extent of bioavailability?

A

AUC, % fluctuation between doses

44
Q

Are AUC curves symmetrical?

A

No they are not normally distributed, we can use log transformation to show symmetrical curve

45
Q

What are the current statistical guidelines for BE?

A

Two 1-sided tests (check if bioavailiability of test formulation is either too low or high)

90% CI for the ratio of means between 0.8-1.20

If log-transformed, then 90% CI is set between 80-125%

46
Q

What are the three approaches for bioequivalence comparisons?

A
  • Average BE
  • Population BE
  • Individual BE
47
Q

What is the most common approach for BE comparisons by Health Canada?

A

Average BE

48
Q

What are some characteristics of Average BE comparisons?

A

Most commonly used by Health Canada

Focuses only on comparison of population averages of a BE measure not on its variance

49
Q

What are some characteristics of Population BE comparisons?

A
  • Relies on population estimates
  • Population BE approach determines total variability of the BE measure in population
50
Q

What are some characteristics of Individual BE comparisons?

A
  • Considers the individual
  • Individual BE assesses within-subject variability of T and R products and subject-by-formulation interaction
51
Q

What are some assumptions made by statistical analysis of T and R in bioequivalence studies?

A
  • Normality (log distribution of random variables)
  • Independent (random variables are independent)
  • Homoscedasticity (variance of dependent variable is constant and does not change with independent variable, ex. formulation, subject, period)
52
Q

What is often chosen to be the reference product in BE studies?

A
  • Traditionally the innovator product

These days, the following can also be used:
- Aqueous true solution of drug
- Aqueous solubilized system of the drug
- Aqueous suspension of micronized drug

53
Q

What parameters in PK-BE are clinically relevent?

A

Cmax and AUC

They represent peak exposure and total exposure, respectively

54
Q

What are some characteristics of the Cmax value in BE studies?

A
  1. Influenced by rate and extent of absorption
  2. Measure of “peak exposure”
  3. Metric recommended to evaluate rate of absorption
55
Q

What are some characteristics of AUC value in BE studies?A

A
  1. Influenced by extent of absorption
  2. Measure of total absorption
  3. Metric recommended to evaluate extent of absorption
56
Q

What statistical technique is used to determine within subject variability in BE studies?

A

Confidence Interval Approach

Health Canada requires 90% CI to be calculated for log-transformed Difference-in-mean (DIM) of the AUC

57
Q

What is the bioequivalence range under the 90% confidence interval approach?

A

The standard equivalence criterion is 80-125% of the geometric means for most drugs (exceptions exist, and will be addressed later)

58
Q

What variance component can estimate within subject variabilty (WSV)?

A

Residual variance can be used to estimate within subject variability

59
Q

Within residual variance, what are some other variance components?

A
  • Within subject variance (WSV) in PK (daily variation in ADME processes)
  • Analytical variability
  • WIthin product variability (tablet to tablet)
  • Subject by formulation interaction (patient shows Cmax and AUC values that are widely different between two formulations)
  • Unexplained random variation
60
Q

Review slide 79 to 85 for methods to calculate the 90% confidence interval for BE studies

A
61
Q

When is bioequivalence declared?

A

90% CI falls within the BE limits of 0.8 to 1.25

If BE is declared, now test and reference drug is said to be interchangable

62
Q

What are the required standards for BE in uncomplicated drugs?

A
  • AUCt, AUCi
  • Cmax, Tmax
  • k, half-life
63
Q

What are some types of drugs do not have a uncomplicated BE process?

A
  • Oral Modified Release
  • Narrow Therapeutic Index drugs
  • Non-linear PK drugs
  • Drugs with long half-lives
  • Drugs with a specific time of onset and rate of absorption
  • Critical Dose Drugs
  • Combination products
  • Highly variable drug products
  • Drugs with measurable endogenous levels
  • Drugs for which PD-BE is only appropriate
64
Q

Why do oral modified release formulations have an unconventional BE process?

A
  • Increased likelihood for greater inter-subject variability in bioavailability will occur, including dose-dumping
  • Increased risk of adverse effects depending upon the site of release, absorption, or both
65
Q

For oral modified release formulations, are BE studies only performed in the fasted state?

A

No, bioequivalence should be demonstrated under both fasted and fed conditions

66
Q

What are the BE standards for single oral dose modified release studies?

A

90% CI around the GMR for AUC of T and R should be within the BE limits of 80-125% in both fasting and fed states

GMR of Cmax for T and R formulations should be within 80-125% in fed and fasted states

67
Q

For food-effect bioanalysis, what types of food are used in conjunction with investigational drug?

A

Use high calorie and high fat meals (greatest effect on GIT physiology)

ex. 2 eggs fried in butter, 2 strips of bacon, 2 slices of toast with butter, 2 pieces of hash browns, 240mL whole milk

68
Q

What is the purpose of food-effect bioequivalence studies?

A

Fed BE studies demonstrate BE to R under fed conditions

69
Q

For BE studies, are lower doses of both formulations preferred?

A

No, highest available strengths are preferred

70
Q

In general, how are food-effect BE studies structured?

A
  • Regular SOD Cross-over BE study comparing IR and MR drug products
  • Following 10h of fast, administer drug 30 minutes after starting of meal with 240mL
  • No food allowed for 4 hours post dose
71
Q

What is a common impact of fed state on MR drug and BE comparison with IR product?

A

Fed status results in slower GI transit time and delayed intestinal absorption

72
Q

How is BE proven for drugs with narrow therapeutic indexes?

A
  • Bioavailability is studied at steady state
  • The test drug replaces the reference drug for at least five half-lives before sampling
  • Standardize administration schedule and posture of the patient
  • Parallel rather than cross-over design
73
Q

For drugs that show exponential increase in AUC for relatively smaller increases in dose, what dose strength should be ideally given?

A

Highest strength

74
Q

For the drugs that show saturated response in AUC for relatively smaller increases in doses, what dose strength should be ideally given?

A

Lowest strength

75
Q

What are the additional BE criteria for drugs with long half-lives?

A
  • AUC is measured from 0h to 72h
  • Require very long washout periods (cross-over not practical, replaced with parallel, steady state, use of stable isotopes)
76
Q

What drugs require TDM?

A
  • Cyclosporine
  • Digoxin
  • Flecainide
  • Lithium
  • Phenytoin
  • Sirolimus
  • Tacrolimus
  • Theophylline
  • Warfarin
77
Q

What is the Health Canada definition for Critical Dose Drugs?

A

Drugs where comparatively small differences in dose of concentration can lead to serious therapeutic failures and/or serious adverse drug reactions

78
Q

What are the BE requirements for Critical Dose Drugs?

A
  • 90% CI for AUC of T and R within 90-112% (more stringent for BE vs. other drugs)
  • 90% CI for Cmax of T and R within 80-125%
79
Q

Can BE studies be performed for Critical Dose Drugs in fasted state alone?

A

No, BE must be met in fasted and fed states

80
Q

What is the definition of highly variable drug products?

A

Within-subject coefficient of variation of the applicable AUC for the reference product is greater than 30%

81
Q

What is the the Biopharmaceutics Classification System?

A

It is a scientific framework for classifying drug substance based on aqueous solubility and intestinal permeablity

Predicts in vivo PK performance of drug products (reduce need for human studies)

82
Q

What are the four classes under the Biopharmaceutics Classification System?

A

Class I (high solubility, high permeability)
Class II (low solubility, high permeability)
Class III (high solubility, low permeabilty)
Class IV (low solubility, low permeability)

see slide 128

83
Q

How is solubility determined for the Biopharmaceutical Classification Systems?

A

Solubility is measured at 3 pHs at minimum (1.2, empty stomach; 4.5, fed stomach; 6.8, intestine)

The lowest measured solubility is used to classify the drug under BCS

84
Q

How is permeability determined for the Biopharmaceutical Classification Systems?

A
  • High permeability can be concluded when the absolute bioavailability is more than 85%
  • Caco-2 cells are a good in-vitro approach
85
Q

What is the purpose of assigning drugs under the Biopharmaceutical Classification Systems?

A

The BCS divides drugs into solubility-permeability classes to allow for more clear expectations regarding in vitro-in vivo correlations

86
Q

What are some characteristics of Class I BCS drugs?

A
  • Well absorbed (not many complications)
  • Bioavailability could be low due to first-pass metabolism
  • Rate limiting step is dissolution or gastric emptying(depends on volume and motility)
  • Biowaiver is possible (waive requirement for BE studies)
87
Q

What is a general rule of thumb for whether a specific formulation will be likely granted a biowaiver?

A

Excipients that can affect absorption are within +/- 10% of the total amount of exipient

88
Q

What are some characteristics of Class II BCS drugs?

A

Class II (Low Solubility/HIgh Permeability)
- Absorption is slower vs. Class I
- In vivo dissolution is rate-controlling step
- Drugs are expected to have a variable absorption
- Biowaiver unlikely

89
Q

What are some characteristics of Class III BCS drugs?

A

Class III (High solubility/low permeability)
- Permeability is the rate-limiting step
- Should show very rapid in vitro dissolution characteristics
- Biowaiver possible (highly soluble, not sensitive to changes in formulation)

90
Q

What are some characteristics of Class IV BCS Drugs?

A

Class IV (Low Solubility/Low Permeability Drugs)
- Very significant problems for effective oral delivery
- Dissolution profiles, solubilities can be determined
- Poor intestinal permeability
- Biowaiver not considered

91
Q

For drugs with narrow therapeutic ranges, are biowaivers possible?

A

No

92
Q
A

PHAR 225 (6 decks)

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