This document discusses bioavailability and bioequivalence studies. It provides details on key pharmacokinetic parameters like AUC, Cmax, and Tmax that are evaluated in bioequivalence studies to determine if a generic drug is equivalent to a brand name drug. The document outlines current bioequivalence requirements set by various regulatory agencies like FDA, Health Canada, and others. It also discusses study design considerations, statistical analysis methods, and validation of bioanalytical methods used to evaluate bioequivalence.
An in-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response".
An in-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response".
United State Pharmacopoeia (USP)The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.
Food and Drug Administration (FDA) definitionIVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.
Special concerns in bioavaliblity and bioeqvivalencePradnya Shirude
you will get here special concerns about bioavailability and bioequivalance. it will also give regulations and criteria for bioavalablity and bioeuivalance
A 2004 presentation "Biopharmaceutics and Drug Product Quality: Performance Performance Tests, A Look Into the Future Into the Future. Presented at the USP Annual Scientific Meeting "The Science of Quality" September 26–30, 2004; Sheraton at Woodbridge Place, Iselin, NJ.
Given the rapidly evolving requirement for 'statistical confidence' thought it would be useful to reflect back on this presentation.
Biopharmaceutics Classification System (BCS) & Waiver of BioequivalenceAjaz Hussain
Graduate Lecture at the University of Maryland (August 2012). Learning Objective: Identify and explain how future regulatory applications of BCS may be realized in the context of ‘Quality by Design’.
Updated July 2013.
I wish to thank all the viewers of my Slideshare presentation of the development and application of the US FDA’s BCS Guidance 2000. Over 11K views have been recorded making this the 2nd highest viewed presentation. FDA is expected to issue a revised BCS draft guidance in the next few weeks. Expected changes include the following:
1. Addition of ‘very rapid’ dissolution criteria (>85% in 15 minutes)
2. Change permeability boundary from 90% to 85%
3. Change the pH solubility range from 1 – 7.5 to 1 – 6.8
4. Possibility of changing paddle speed from 50 to 75 rpm.
5. Additional topics / clarification on FDCs (Fixed Dose Combinations), ODTs (Orally Disintegrating Tablets), MR (Modified Release) products.
6. Update the list of model drugs.
7. Strengthen GI stability requirement.
United State Pharmacopoeia (USP)The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.
Food and Drug Administration (FDA) definitionIVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.
Special concerns in bioavaliblity and bioeqvivalencePradnya Shirude
you will get here special concerns about bioavailability and bioequivalance. it will also give regulations and criteria for bioavalablity and bioeuivalance
A 2004 presentation "Biopharmaceutics and Drug Product Quality: Performance Performance Tests, A Look Into the Future Into the Future. Presented at the USP Annual Scientific Meeting "The Science of Quality" September 26–30, 2004; Sheraton at Woodbridge Place, Iselin, NJ.
Given the rapidly evolving requirement for 'statistical confidence' thought it would be useful to reflect back on this presentation.
Biopharmaceutics Classification System (BCS) & Waiver of BioequivalenceAjaz Hussain
Graduate Lecture at the University of Maryland (August 2012). Learning Objective: Identify and explain how future regulatory applications of BCS may be realized in the context of ‘Quality by Design’.
Updated July 2013.
I wish to thank all the viewers of my Slideshare presentation of the development and application of the US FDA’s BCS Guidance 2000. Over 11K views have been recorded making this the 2nd highest viewed presentation. FDA is expected to issue a revised BCS draft guidance in the next few weeks. Expected changes include the following:
1. Addition of ‘very rapid’ dissolution criteria (>85% in 15 minutes)
2. Change permeability boundary from 90% to 85%
3. Change the pH solubility range from 1 – 7.5 to 1 – 6.8
4. Possibility of changing paddle speed from 50 to 75 rpm.
5. Additional topics / clarification on FDCs (Fixed Dose Combinations), ODTs (Orally Disintegrating Tablets), MR (Modified Release) products.
6. Update the list of model drugs.
7. Strengthen GI stability requirement.
Bioavailability and Bioequivalence StudiesPranav Sopory
BA and BE studies.
Seminar presented in All India Institute of Medical Sciences (AIIMS - New Delhi).
Focus in Pharmacokinetic parameters (Cmax, AUC)
Single dose PK study, Steady state PK study, Modified drug release PK study, In vivo mechanisms, invitro mechanisms, Pharmacodynamic Study, Comparatice Clinical Trials. Biowavers and Biosimilimars.
Reference: CDSCO guideline, USFDA guideline, ICH guidelines
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
Follow us on: Pinterest
Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
3. Ensuring uniformity in standards of
quality, efficacy of pharmaceutical
products.
BA/BE focus on the release of the
drug from the dosage form and
absorption in to the systemic
circulation.
BE for the comparison of the two drug,
several test method are given to
determine the equivalence.
4. Important Pharmacokinetic
Parameters
AUC: area under the concentration-time
curve measure of the extent of
bioavailability
Cmax: the observed maximum
concentration of drug measure of both
the rate of absorption and the extent of
bioavailability
tmax: the time after administration of drug
at which Cmax is observed measure of
the rate of absorption
6. BIOAVAILABILITY: It is relative amount
of drug from an administered dosage
form which enters the systemic
circulation and rate at which the drug
appears in the systemic circulation.
The extent and rate at which its active
moiety is delivered from pharmaceutical
form and becomes available in the
systemic circulation
7. Scheme of Oral Dosage Form
Oral Bioavailability (%F)
Human Intestinal
Absorption (HIA)
1,2 – Stability + Solubility
3 – Passive + Active Tr.
4 – Pgp efflux + CYP 3A4
8. Why do we care about
BIOAVAILABILITY?
The “true dose” is not the drug swallowed;
BUT is the drug available to exert its effect,
• Dissolution
• Absorption
• Survive metabolism
9. Why do we care about
BIOAVAILABILITY?
May have a drug with very low bioavailability.
• Dosage form or drug may not dissolve readily.
• Drug may not be readily pass across biological
membranes (i.e. be absorbed).
• Drug may be extensively metabolized during
absorption process (first-pass, gut wall, liver).
Important component of overall variability
i.e. Variable bioavailability may produce variable
exposure.
10. Pharmaceutical Equivalents
contain the same amount of the same
active substance in the same dosage form
meet the same or comparable standards
intended to be administered by the same
route
Pharmaceutical equivalence by itself does
not
necessarily imply therapeutic equivalence
11. Pharmaceutical Equivalents
Test Reference
Possible Differences
Drug particle size
Excipients
Manufacturing Equipment or Process
Site of manufacture
Could lead to differences in product performance
in vivo
Possible Bioinequivalence
12. Bioequivalence
Two products are bioequivalent if
they are pharmaceutically equivalent
bioavailabilities (both rate and extent)
after administration in the same molar
dose are similar to such a degree that
their effects can be expected to be
essentially the same
13. Therapeutic equivalence
Two products are therapeutically equivalent if
pharmaceutically equivalent
their effects, with respect to both efficacy and
safety, will be essentially the same as derived from
appropriate studies
◦ bioequivalence studies
◦ pharmacodynamic studies
◦ clinical studies
◦ in vitro studies
14. Bioequivalence (BE):
the absence of a significant difference in
the rate
and extent to which the active ingredient
or active
moiety in pharmaceutical equivalents or
pharmaceutical alternatives becomes
available at
the site of drug action when administered
at the
same molar dose under similar conditions
in
an appropriately designed study
15. Need of bioequivalence
studies
No clinical studies have been
performed in patients with the Generic
Product to support its Efficacy and
Safety.
With data to support similar in vivo
performance (= Bioequivalence)
Efficacy and Safety
data can be extrapolated from the
Innovator Product to the Generic
Product.
16. Bioequivalence (BE):
Ultimate: Bioequivalence studies impact
of changes to the dosage form process
after pivotal studies commence to
ensure product on the market is
comparable to that upon which the
efficacy is based
Establish that a new formulation has therapeutic
equivalence in the rate and extent of absorption to
the reference drug product.
Important for linking the commercial drug product
to clinical trial material at time of NDA.
Important for post-approval changes in the
marketed drug formulation.
18. Goals of BE
Ultimate: Bioequivalence studies impact
of changes to the dosage form process
after pivotal studies commence to
ensure product on the market is
comparable to
that upon which the efficacy is based
Establish that a new formulation has therapeutic
equivalence in the rate and extent of absorption to
the reference drug product.
Important for linking the commercial drug product
to clinical trial material at time of NDA
Important for post-approval changes in the
marketed drug formulation
19. NDA vs. ANDA Review
Process
Innovator and generic drug
Original Drug
NDARequirements
1. Chemistry
2. Manufacturing
3. Controls
4. Labeling
5. Testing
6. Animal Studies
7. Clinical Studies
(Bioavailability/Bioequivalence)
Generic Drug
ANDARequirements
1. Chemistry
2. Manufacturing
3. Controls
4. Labeling
5. Testing
6. Bioequivalence Study (In
Vivo, In vitro)
20. NDA vs. ANDA Review
Process
Note: Generic drug applications are
termed "abbreviated" because they are
generally
not required to include preclinical
(animal) and clinical (human) data to
establish safety and effectiveness.
Instead, generic applicants must
scientifically demonstrate that their
product is bioequivalent
(i.e., performs in the same manner as the
original; drug).
21. 21
Current BE* Requirements
Major Regulatory Agencies
U.S. Food and Drug Administration
(FDA)
Health Canada
Committee for Proprietary Medicinal
Products (CPMP), Europe
National Institute of Health Sciences
(NIHS), Japan
*BE = Bioequivalence
22. 22
Current BE Requirements
FDA*
AUC: 90% Confidence Interval Limits
80-125%
Cmax: 90% Confidence Interval Limits
80-125%
Criteria applied to drugs of low and
high variability
23. 23
Current BE Requirements
Health Canada
AUC: 90% Confidence Interval Limits
80-125%
Cmax: Mean T/R ratio (point estimate)
between 80-125% (T=test,
R=reference)
Criteria judged flexible enough to deal
with highly variable drugs*
24. 24
Current BE Requirements
CPMP*
AUC: 90% Confidence Interval Limits
80-125%
Cmax: 90% Confidence Interval Limits
80-125%
Cmax: “In certain cases a wider interval
is acceptable (e.g., 75-133%)
25. 25
Current BE Requirements
NIHS (Japan)*
AUC: 90% Confidence Interval Limits
80-125%
Cmax: 90% Confidence Interval Limits
80-125%
In cases of failure, add-on studies are
acceptable (provided other criteria are
met)
26. Study Design: Basic design
consideration
Minimize variability to formulations
Minimize bias
To compare performance of two
products!!!
28. Study Designs
Duration of washout period for cross-
over design
- should be approximately > 5 times the
plasma apparent terminal half-life
- However, should be adjusted
accordingly for drugs with complex
kinetic model
29. Study Designs
Sample size determination(dose)
- significant level (α = 0.05)
- 20% deviation from the reference
product
- power > 80%
Sample time determination
- adequate data points around tmax
- 3 or more time of t1/2 to around AUC0-t
= at least 80% AUC0-inf
30. Study Designs
Subjects? (Inclusion/exclusion criteria)
LABEL
Healthy subjects (male and female)
18-55 years old,
Non-smokers/without a history of alcohol or drug
abuse Medical history/Clinical Lab test values
must be within normal ranges
Contraindication
Refrain from the concomitants use of any
medications or food interact with GI, renal, liver
function from 28 days prior study Day1
through the safety.
31. Study Design:
Crossover Design
x Crossover design
A single-dose bioequivalence study is
performed in normal, healthy, adult
volunteers.
18 subjects are hired (Male or Female?)
The subjects are randomly selected for
each group and the sequence of drug
administration is randomly assigned.
One-week washout periods
Fasted or Fed?
32. Statistical Analysis
(Two one-sided
Tests Procedure)
AUC (Extent) and Cmax (Rate) – Log
transformation
i.e. 90% Confidence Intervals (CI) of the
difference in Log (AUCt) –Log (AUCR)
must fit between 80%-125%
34. Bioanalytical Method
Validation
Accuracy
Closeness of determined value to the
true
Value
The acceptance criteria is mean value <
15% deviation from the true value.
At LOQ(limit of quantification), 20%
deviation is acceptable
35. Bioanalytical Method
Validation
Precision
The closeness of replicate
determinations of
a sample by an assay
The acceptance criteria is < 15%
CV,(closeness value) at
20% LOQ(limit of quantification)
36. Bioanalytical Method
Validation
Sensitivity
The limit of quantitation is the lowest
concentration which can be measured
with acceptable accuracy and precision
Selectivity
Ability of the method to measure only what
it
is intended to measure in the presence of
other components in the sample. Blank
samples of the biological matrix should be
tested for the interfering peak.
37. Bioanalytical Method
Validation
Recovery
The extraction efficiency of an analytical
process, reported as an percentage of
the
known amount of an analyte. Recovery
does not have to be 100% but the
extent of recovery of internal standard
and analyte should be consistent.
39. Conclusion
Establish that a new formulation has
therapeutic equivalence in the rate
and extent of absorption to the
reference drug product.
Important for linking the commercial
drug product to clinical trial material at
time of NDA.
Important for post-approval changes
in the marketed drug formulation.