Bioequivalence studies for various pharmaceutical drug formulations manufactured and released into the market is outlined in this presentation. The various studies used to establish bioequivalency with the original formulation is also mentioned.
The release of the drug substance from the drug product leading to the bioavailability of the drug substance. The assessment of drug product performance is imp. Since bioavailability is related both to the pharmacodynamic responses and the adverse events. The performance tests relate the quality of a drug product to clinical safety and efficacy.
Bioavailability studies are drug product performance studies used to define
the effect of changes in the physicochemical properties of the drug substance, the formulation of the drug, and the manufacturing process of the drug product.
Bioequivalence studies for various pharmaceutical drug formulations manufactured and released into the market is outlined in this presentation. The various studies used to establish bioequivalency with the original formulation is also mentioned.
The release of the drug substance from the drug product leading to the bioavailability of the drug substance. The assessment of drug product performance is imp. Since bioavailability is related both to the pharmacodynamic responses and the adverse events. The performance tests relate the quality of a drug product to clinical safety and efficacy.
Bioavailability studies are drug product performance studies used to define
the effect of changes in the physicochemical properties of the drug substance, the formulation of the drug, and the manufacturing process of the drug product.
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
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.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
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.
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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
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
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Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
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- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
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Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
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.
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
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2. Drug Product Performance
The release of the drug substance from the drug product
leading to bioavailability of the drug substance.
The assessment of drug product performance is important
since bioavailability is related both to the
pharmacodynamic response and to adverse events.
Drug product performance studies are used in the
development of new and generic drug products
Dr. Muhammad Usman 2
3. Bioavailability
• Bioavailability is defined as the rate and extent at
which active drug reaches to the site of action from
it’s dosage form.
• It provides the estimation of fraction of drug
absorbed from formulation
• BA depends on
1. Pharmaceutical factors
2. Patient related factors
3. Rout of administration
Dr. Muhammad Usman 3
Types of
Bioavailability
Absolute
Bioavailability
Relative
Bioavailability
4. Absolute Bioavailability
(F)
When the bioavailability of a drug administered orally is
determined by its comparison to IV administration is
called Absolute Bioavailability.
It is determined to characterize the drug’s inherent
absorption properties from extra-vascular rout.
The value is always ≤ 1
Dr. Muhammad Usman 4
Absolute Bioavailability =
[AUC]oral × Dose{IV
[AUC]IV ×Dose Oral
× 100
or ≤ 100%
5. Relative Bioavailability
(Fr)
When the systemic absorption of one drug product is compared
with other formulation is called as Relative Bioavailability.
It is determined to compare the relative absorption properties of
two different formulations.
Bioequivalence is a specialized for of Relative BA.
Relative Bioavailability may be less than or greater than 100
Dr. Muhammad Usman 5
Relative Bioavailability =
[AUC]A × Dose{B
× 100
[AUC]B ×Dose A
7. Pharmaceutical Equivalents:
Two drug products are deemed to be pharmaceutical
equivalents if they have the same active ingredient(s),
strength or concentration, dosage form, and route of
administration.
Bioequivalents:
Bioequivalence is defined as the absence of a significant
difference in the rate and extent to which the active
ingredient becomes available at the site of drug action
when administered at the same molar dose under similar
conditions in an appropriately designed study.
Dr. Muhammad Usman 7
8. Therapeutic Equivalents:
Drugs products are considered to be therapeutic
equivalent only if they are pharmaceutical equivalent
and have same clinical effect and safety profile when
administered to the patients under the conditions
specified in the labeling
Dr. Muhammad Usman 8
Pharmaceutical
Equivalent
Bioquivalent
Therapeutic
Equivalent
9. Bioequivalence Studies during drug
development
• In New Drug Development (NDA) BE studies are used
to;
1. Early and late clinical trial formulations
2. Formulations used in clinical trials and stability
studies
3. Clinical trial formulation and to be marketed as drug
product (Post approval changes)
SUPAC (Scale-up and post approval changes)
4. Product strength equivalent
5. To support new formulation of previously approved
product
Dr. Muhammad Usman 9
11. Bioequivalence Studies in Generic Drug
Development (ANDA)
• Comparative drug product performance studies are
important in the development of generic drug products
A generic drug product is a multisource drug product
that has been approved by the FDA as a therapeutic
equivalent to the reference listed drug product.
• Clinical safety and efficacy studies are not generally
performed on generic drug products
• The generic drug manufacturer must demonstrate that
the generic drug product is pharmaceutically equivalent,
bioequivalent, and therapeutically equivalent to the
comparator brand-name drug product.
Dr. Muhammad Usman 11
12. Dr. Muhammad Usman 12
Bioequivalence Studies in Generic Drug
Development (ANDA)
Sharjel 7th Edition Page No. 471
13. Bioequivalence study
Dr. Muhammad Usman 13
Product A
AUC
Cmax
Tmax
T1/2
CL
AUC
Cmax
Tmax
T1/2
CL
Statistically
Significant
Statistically
Inignificant
Difference
Not
Bioequivalent
Bioequivalent
Product B
AUC
Cmax
Tmax
T1/2
CL
AUC
Cmax
Tmax
T1/2
CL
AUC
Cmax
Tmax
T1/2
CL
AUC
Cmax
Tmax
T1/2
CL
AUC
Cmax
Tmax
T1/2
CL
AUC
Cmax
Tmax
T1/2
CL
AUC
Cmax
Tmax
T1/2
CL
AUC
Cmax
Tmax
T1/2
CL
Wash out
Cross Over study
14. Dr. Muhammad Usman 14
Product A
AUC
Cmax
Tmax
T1/2
CL
AUC
Cmax
Tmax
T1/2
CL
Statistically
Significant
Difference
AUC
Cmax
Tmax
T1/2
CL
AUC
Cmax
Tmax
T1/2
CL
AUC
Cmax
Tmax
T1/2
CL
AUC
Cmax
Tmax
T1/2
CL
AUC
Cmax
Tmax
T1/2
CL
AUC
Cmax
Tmax
T1/2
CL
AUC
Cmax
Tmax
T1/2
CL
AUC
Cmax
Tmax
T1/2
CL
Group A Group B
Parallel study
Not
Bioequivalent
Bioequivalent
Product B
Statistically
Inignificant
16. Methods for assessing BA and BE
The FDA’s regulations (US-FDA, CDER, 2014a) list the
following approaches to determining bioequivalence.
1. In vivo measurement of active moiety in biological fluids.
2. In vivo pharmacodynamics comparison
3. In vivo clinical comparison
4. In vitro comparison
For drug products that are not intended to absorbed into
the blood stream, bioavailability may be assessed by rate
and extent to which drug becomes available at the site of
action
Dr. Muhammad Usman 16
17. • This is most sensitive, accurate and reproducible
approach.
• For all systemically active drugs (with few
exceptions), BE should be demonstrated by in
vivo study based on pharmacokinetic endpoints
• Two approaches
1) Plasma drug concentration
2) Urinary excretion data
Dr. Muhammad Usman 17
In vivo measurement of active
moiety in biological fluids.
18. • Plasma Drug Concentration
This is most direct and appropriate way to
measure the systemic bioavailability
Parameters:
tmax (h)
Measure of rate of drug absorption
At tmax the rate of drug absorption becomes equal to
the rate of elimination
Dr. Muhammad Usman 18
In vivo measurement of active
moiety in biological fluids.
19. Cmax (mg/L or µg/mL or ng/mL)
• Relates with the pharmacodynamics (therapeutic and toxic)
effects of drugs
• Although not has a unit of rate but is used in BE studies as a
measure of rate of drug absorption
AUC (mg.h/L)
• Measure of extent of drug absorption
• Independent of rout of administration and process of drug
elimination
Dr. Muhammad Usman 19
In vivo measurement of active
moiety in biological fluids.
20. • For many drugs, AUC is directly proportional to dose
Dr. Muhammad Usman 20
In vivo measurement of active
moiety in biological fluids.
21. • In some cases, AUC is not directly proportional to dose e-g
Salicylates, Phenytoin
Dr. Muhammad Usman 21
In vivo measurement of active
moiety in biological fluids.
22. • Urinary Drug Excretion Data
Indirect estimation of bioavailability
Du is the cumulative amount of drug excreted in urine
Dr. Muhammad Usman 22
In vivo measurement of active
moiety in biological fluids.
23. PD comparison is used in the cases where quantitative measurement
of plasma drug concentration is not available or in vitro approaches
are not applicable.
• A dose response relationship is demonstrated.
• The PD effect should be at rising phase of dose response curve
• Sufficient measurements should be taken to assure an appropriate
PD response.
• All PD measurement assays should be validated for specificity,
accuracy, sensitivity and precision.
• Two approaches
1. Demonstration of dose response curve
2. Acute pharmacodynamics effect-time curve
Dr. Muhammad Usman 23
In vivo Pharmacodynamic
comparison
24. Dr. Muhammad Usman 24
Dose-Response Curve
Pharmacodynamics effect-time curve
26. • A parallel BE study
• Least accurate, least sensitive to bioavailability difference
• A predetermined clinical endpoint is used to evaluate the
clinical effect in the patients
• Requires the use of large number of patients which increases
cost and duration of study.
• Placebo arm is usually included
• Recommended for the products which;
1. Have negligible systemic absorption
2. For which there is no identified PD measure
3. For which site of action is local
Dr. Muhammad Usman 26
In vivo comparison based on
clinical end point
28. • Dissolution studies
• Should Correlate in vivo bioavailability
• Comparative dissolution studies are often
performed on several test formulations of
the same drug during drug development.
• Under certain conditions, comparative dissolution
profiles of higher and lower dose strengths of a
solid oral drug product such as an immediate-
release tablet are used to obtain a waiver
(biowaiver) of performing additional in vivo
bioequivalence studies.
Dr. Muhammad Usman 28
In vitro studies
29. • The use of in vitro biomarkers and in vitro binding studies
• Examples
1. The bioequivalence of cholestyramine resin is performed
by equilibrium and kinetic binding studies of the resin to bile
acid salts
2. For calcium acetate tablets, the FDA recommends a
relatively simple in vitro binding assay based on the
test/reference binding ratio over a range of phosphate
concentrations.
3. Comparative in vitro release testing and physicochemical
characterization for Acyclovir topical ointment
Dr. Muhammad Usman 29
Other approaches
34. Statistical evaluation of data
• Bioequivalence is generally determined using a
comparison of population averages of a
bioequivalence metric, such as AUC and Cmax.
• This approach, termed average bioequivalence,
involves the calculation of a 90% confidence
interval for the ratio of averages.
• To establish bioequivalence, both AUC and Cmax
for the test (generic) product should be within
80%–125% of the reference product using a 90%
confidence interval.
Dr. Muhammad Usman 34
36. Multiple-Dose (Stady-State) Study Design
• A bioequivalence study may be performed using a multiple-dose
study design.
• A steady-state, randomized, two-treatment, two-way, crossover
study comparing equal doses of the test and reference products
in healthy adult subjects.
• Three consecutive trough concentrations (Cmin) are
determined to ascertain that the subjects are at steady state.
• The last morning dose is given to the subject after an overnight
fast, with continual fasting for at least 2 hours following dose
administration.
• Blood sampling is then performed over one dosing interval
Dr. Muhammad Usman 36
38. Pharmacokinetic analyses for multiple-dose studies
include calculation of the following parameters for
each subject:
AUC 0-tau (Area under the curve during a dosing interval)
tmax (Time to Cmax during a dosing interval)
Cmax (Maximum drug concentration during dose interval)
Cmin (Concentration at the end of a dose interval)
Cav During dose interval
Degree of fluctuation = (Cmax- Cmin)/Cmax
Swing = (Cmax- Cmin)/Cmin
Dr. Muhammad Usman 38
Multiple-Dose (Stady-State) Study Design
39. Advantages:
Determination of bioavailability using multiple doses reveals changes that
are normally not detected in a single-dose study. e.g Non-linear
Pharmacokinetics, may be observed by rising Cmin and AUC after each
dose interval.
Disadvantages:
1. Time consuming and may lead to high cost and possibility of dropping
out of volunteers
2. More blood samples
3. Small differences in the rate of drug absorption may not be observed
with steady-state study comparisons Because Cav
∞ depends primarily
on the dose of the drug and the time interval between doses, the
extent of absorption is more important than rate.
Dr. Muhammad Usman 39
Multiple-Dose (Stady-State) Study Design
40. • A randomized, double-blind, placebo controlled, parallel-
designed study comparing test product, reference product,
and placebo product in patients.
• A placebo arm is usually included to demonstrate that the
treatments are active and the study is sufficiently sensitive
to identify the clinical effect in the patient population
enrolled in the study.
• In some cases, the use of a placebo may not be included for
safety reasons.
• The primary analysis for bioequivalence is determined by
evaluating the difference between the proportion of
patients in the test and reference treatment groups who
are considered a “therapeutic cure” at the end of study
Dr. Muhammad Usman 40
Clinical End-Point BE Study
41. • Due to safety concern, some drugs such as antipsychotic drugs, anti-
cancer drugs etc. can not be given to healthy individuals.
• BE should be performed in patients who have been stabilized on
highest strength using multiple dose BE study.
• No wash out period can be given.
• The patient is maintained on previous dose of medication and blood
sampling is performed during a dose interval.
• Without washout, the patient takes equal dose of test or reference
product and previous drug product is discontinued.
• Dosing with each drug product is continued till steady state is
attained.
• The plasma level time curve for second drug product is obtained
Dr. Muhammad Usman 41
BE of drug products in patients
42. • Bioequivalence or absence of bioequivalence is
determined by comparison of both plasma level
time curve data.
• The patient then continues with original drug
product.
• Products are given in a random order e.g “A” then
“B” and “B” then “A”.
• The reference product is provided by the
investigator from a known lot (not from patient’s
prescription)
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BE of drug products in patients
44. Clinical Examples
Levothyroxine Sodium Oral Tablets
• A multiple dose relative bioavailability study of two synthetic branded
levothyroxine sodium oral tablets, product A and product B, were evaluated
in 20 euthyroid patients.
• The investigation was designed as a two-way crossover study in which the
patients who had been diagnosed as hypothyroid by their primary-care
physician were given a single 100-mg daily dose of either product A or
product B levothyroxine sodium tablets for 50 days and then switched over
immediately to the other treatment for 50 days.
• Pre-dose blood samples were taken on days 1, 25, 48, 49, and 50 of each
phase, and, on day 50, a complete blood sampling was performed.
• The serum from each blood sample was analyzed for total and free thyroxine
(T4), total and free triiodothyronine (T3), the major metabolite of T4, and
thyrotropin (TSH).
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45. Levothyroxine Sodium Oral Tablets
a) Why were hypothyroid patients used in this study?
Answer: Normal healthy euthyroid subjects would be at risk if they were to take
levothyroxine sodium for an extended period of time.
b) Why were the subjects dosed for 50 days with each thyroid product?
Answer: The long (50-day) daily dosing for each product was required to obtain
steady-state drug levels because of the long elimination half-life of levothyroxine.
c) Why were blood samples obtained on days 48, 49, and 50?
Answer: Serum from blood samples was taken on days 48, 49, and 50 to obtain
three consecutive Cmin drug levels.
d) Why was T3 measured?
Answer: T3 is the active metabolite of T4.
e) Why was TSH measured?
Answer: The serum TSH concentration is inversely proportional to the free
serum T4 concentrations and gives an indication of the pharmacodynamic activity
of the active drug.
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46. Dr. Muhammad Usman 46
Mercaptopurine (Purinethol) Oral Tablets
• The FDA recommends BE steady-state studies in patients receiving
therapeutic oral doses.
• Patients should be on a stable regimen using the same dosage unit
• Plasma drug concentration–time profiles are obtained in these
patients at steady state with the brand product.
• The proposed generic drug product is then given to these patients
at the same dosage regimen until steady state is reached.
• Plasma drug concentration–time profiles are obtained for the
generic drug product;
• Then the patients return to the original brand medication
Clinical Examples
47. Design and evaluation of
Bioequivalence Studies
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Team
Pharmacokinetists Clinicians Bio-Analysts Statistician Others
Nurses Phlebotomist
Technicians Helpers
48. Design and evaluation of
Bioequivalence Studies
I. Title
A. Principal investigator (Study Director)
B. Project Protocol number and date
II. Study Objective
• Should be clearly stated.
• Considerations
1. The scientific questions and objectives to be answered,
2. The nature of the reference material and the dosage form to be tested,
3. The availability of analytical methods,
4. The pharmacokinetics and pharmacodynamics of the drug substance,
5. The route of drug administration, and
6. Benefit–risk and ethical considerations with regard to testing in humans.
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49. III. Study Design
A. Design (Cross over, Parallel etc)
B. Drug Products
1. Test Product(s)
2. Reference Product (RLD)
C. Dosage Regimen
D. Sample Collection Schedule
E. Housing and Confinement
F. Fasting and Meal Schedule
G. Analytical methods
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Design and evaluation of
Bioequivalence Studies
50. IV. Study Population
A. Subjects (healthy Volunteers, Patients etc)
B. Subject selection
1. Medical history
2. Physical examination
3. Laboratory tests
C. Inclusion/Exclusion criteria
D. Restrictions/Prohibitions
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Design and evaluation of
Bioequivalence Studies
51. V. Clinical Procedures
A. Dosage and drug administration
B. Biological sampling schedule and handling procedures
1. Vials coding
2. Sample collection
3. Plasma separation
4. Precautions
5. Record keeping
C. Activity of subjects
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Design and evaluation of
Bioequivalence Studies
52. VI. Ethical Procedures
A. Basic principles
B. Institutional Review Board
C. Informed Consent
D. Indications for subject withdrawal
C. Adverse reaction and emergency procedures
VII. Facilities
VIII. Data analysis
A. Analytical validation procedures
B. Statistical treatment of data
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Design and evaluation of
Bioequivalence Studies
53. Study submission and
review process
The submission for an NDA must contain safety
and efficacy studies as provided by
Animal toxicology studies,
Clinical efficacy studies, and
Pharmacokinetic/bioavailability studies.
For submission of ANDA (generic drug
manufacture), the BE study replaces the Animal,
Clinical and PK studies.
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55. • The investigator should be sure that the study has
been properly designed, the objectives are clearly
defined, and the method of analysis has been
validated.
• These results, along with case reports and various
data supporting the validity of the analytical
method, are included in the submission
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Study submission and
review process
56. • The FDA reviews the study in details based on the
following outline;
1. Introduction
2. Study design
3. Study objectives
4. Assay description and validation
5. Summary and analysis of data
6. Comments
7. Deficiencies
8. Recommendations
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Study submission and
review process
57. Dr. Muhammad Usman 57
Applicant
ANDA
Refused to file and
letter issued
Bioequivalence deficiency
letter
Not approvable letter
Approval deferred pending
satisfactory Results
ANDA Approved
Request for plant inspection
Chemistry,
Labeling review
acceptable
Preapproval
inspection
Applicable?
BE review
acceptable?
Yes
No
Applicable
and
complete?
Labeling review
Review by OGD/CDER
Bioequivalence Review
Chemistry/Micro Review
Yes
No No
No
Yes