Dr. Paul Frohna, a biotech consultant with expertise in translational medicine and clinical pharmacology, presents an overview of the FDA's evolving perspectives on the QTc issue and the stand alone thorough QTc study.
PK/PD and Immunogenicity Conferences, May 2014, Boston, MA - part of PEGSJames Prudhomme
The Safety Stream at PEGS will guide attendees through the process of developing a comprehensive immunogenicity and PK/PD strategy to ensure successful biologics. With a focus on novel constructs, high level science and expert advice will examine assay strategies, management of product immunogenicity, and modeling PK/PD to improve drug performance. Risk assessment and regulatory guidance to ensure clinical success and a competitive advantage will also be addressed.
PK/PD and Immunogenicity Conferences, May 2014, Boston, MA - part of PEGSJames Prudhomme
The Safety Stream at PEGS will guide attendees through the process of developing a comprehensive immunogenicity and PK/PD strategy to ensure successful biologics. With a focus on novel constructs, high level science and expert advice will examine assay strategies, management of product immunogenicity, and modeling PK/PD to improve drug performance. Risk assessment and regulatory guidance to ensure clinical success and a competitive advantage will also be addressed.
Translational Genomics and Prostate Cancer: Meet the NGS Experts Series Part 2QIAGEN
Advanced prostate cancer is highly heterogeneous but this inter-patient heterogeneity has until recently not been understood. We have through an international research effort dissected the molecular landscape of advanced castration resistant prostate, elucidating key molecular targets in this group of diseases. We have also shown that PARP inhibitors have antitumor activity against a significant proportion of these cancers, mainly in men whose cancers harbor DNA repair defects.
Immunotherapy for Metastatic Triple Negative Breast Cancerbkling
Sylvia Adams, MD, medical oncologist, and associate professor at the NYU School of Medicine, discusses the latest research including the role of immunology in the treatment of triple negative metastatic breast cancer. This webinar was hosted on October 19, 2016.
Tenecteplase is a newer generation tissue plasminogen activator which can be given as a bolus dose than continuous infusion. Genentech, the same company that manufactures Alteplase makes Tenecteplase. Phase 2 RCTs have been done on Tenecteplase comparing its feasibility and safety against Alteplase and so far the studies have been encouraging. In a pooled meta analysis from the Australian TNKase trial and ATTEST trials, tenecteplase seems to be better in recanalizing LVO compared to Alteplase which also showed to improve functional outcome in the first 24hrs and 3 months mRS. But it is difficult to extrapolate the evidence into clinical practice yet as this is a very small number of patients and phase 3 RCTs will answer further questions. This tPA sibling to Alteplase is cheaper and widely available due to its use in Acute coronary syndrome management and its ease of administration demonstrate better profile. But as Genentech is the same company that manufactures both, there is skepticism that it will do any company led phase 3 RCTs to build the evidence for TNKase in Acute ischemic stroke as it is cheaper than Alteplase and they even increased the price of alteplase to >100% since its introduction into the market.
Here is the updated list of Top Best Ayurvedic medicine for Gas and Indigestion and those are Gas-O-Go Syp for Dyspepsia | Lavizyme Syrup for Acidity | Yumzyme Hepatoprotective Capsules etc
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
More Related Content
Similar to Paul frohna -PK-PD Modeling and the QTc Issue (part 2- Approaches to QTc Evaluation During Clinical Development)
Translational Genomics and Prostate Cancer: Meet the NGS Experts Series Part 2QIAGEN
Advanced prostate cancer is highly heterogeneous but this inter-patient heterogeneity has until recently not been understood. We have through an international research effort dissected the molecular landscape of advanced castration resistant prostate, elucidating key molecular targets in this group of diseases. We have also shown that PARP inhibitors have antitumor activity against a significant proportion of these cancers, mainly in men whose cancers harbor DNA repair defects.
Immunotherapy for Metastatic Triple Negative Breast Cancerbkling
Sylvia Adams, MD, medical oncologist, and associate professor at the NYU School of Medicine, discusses the latest research including the role of immunology in the treatment of triple negative metastatic breast cancer. This webinar was hosted on October 19, 2016.
Tenecteplase is a newer generation tissue plasminogen activator which can be given as a bolus dose than continuous infusion. Genentech, the same company that manufactures Alteplase makes Tenecteplase. Phase 2 RCTs have been done on Tenecteplase comparing its feasibility and safety against Alteplase and so far the studies have been encouraging. In a pooled meta analysis from the Australian TNKase trial and ATTEST trials, tenecteplase seems to be better in recanalizing LVO compared to Alteplase which also showed to improve functional outcome in the first 24hrs and 3 months mRS. But it is difficult to extrapolate the evidence into clinical practice yet as this is a very small number of patients and phase 3 RCTs will answer further questions. This tPA sibling to Alteplase is cheaper and widely available due to its use in Acute coronary syndrome management and its ease of administration demonstrate better profile. But as Genentech is the same company that manufactures both, there is skepticism that it will do any company led phase 3 RCTs to build the evidence for TNKase in Acute ischemic stroke as it is cheaper than Alteplase and they even increased the price of alteplase to >100% since its introduction into the market.
Here is the updated list of Top Best Ayurvedic medicine for Gas and Indigestion and those are Gas-O-Go Syp for Dyspepsia | Lavizyme Syrup for Acidity | Yumzyme Hepatoprotective Capsules etc
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
share - Lions, tigers, AI and health misinformation, oh my!.pptxTina Purnat
• Pitfalls and pivots needed to use AI effectively in public health
• Evidence-based strategies to address health misinformation effectively
• Building trust with communities online and offline
• Equipping health professionals to address questions, concerns and health misinformation
• Assessing risk and mitigating harm from adverse health narratives in communities, health workforce and health system
These lecture slides, by Dr Sidra Arshad, offer a quick overview of the 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 lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
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. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
Title: Sense of Taste
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 structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Integrating Ayurveda into Parkinson’s Management: A Holistic ApproachAyurveda ForAll
Explore the benefits of combining Ayurveda with conventional Parkinson's treatments. Learn how a holistic approach can manage symptoms, enhance well-being, and balance body energies. Discover the steps to safely integrate Ayurvedic practices into your Parkinson’s care plan, including expert guidance on diet, herbal remedies, and lifestyle modifications.
ABDOMINAL TRAUMA in pediatrics part one.drhasanrajab
Abdominal trauma in pediatrics refers to injuries or damage to the abdominal organs in children. It can occur due to various causes such as falls, motor vehicle accidents, sports-related injuries, and physical abuse. Children are more vulnerable to abdominal trauma due to their unique anatomical and physiological characteristics. Signs and symptoms include abdominal pain, tenderness, distension, vomiting, and signs of shock. Diagnosis involves physical examination, imaging studies, and laboratory tests. Management depends on the severity and may involve conservative treatment or surgical intervention. Prevention is crucial in reducing the incidence of abdominal trauma in children.
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
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Paul frohna -PK-PD Modeling and the QTc Issue (part 2- Approaches to QTc Evaluation During Clinical Development)
1. PK-PD Modeling with the QTc:
Is it possible to avoid a TQT Study?
Part 2. Approaches to QTc Evaluation During
Clinical Development
Paul A. Frohna, MD, PhD, PharmD
Biotechnology Consultant
Frohna Biotech Consulting
www.frohnabiotechconsulting.com
2. Approaches to QTc Evaluation
During Clinical Development
Role of PK-PD
Recent Examples and Outcomes
3. The Learn-Confirm Approach for
QTc Assessment
Learn: Collect ECG data in Phase I/IIa for
exposure-response analysis with PK and DQTc
– Requires advanced planning
– Helps determine Phase III ECG monitoring frequency
– Risk reduction strategy
Confirm: Design your TQT study based on your
―Learn‖ analysis
– May allow smaller sample sizes
May be acceptable to regulatory authorities
when a TQT study is infeasible or when
significant amounts of QTc data have already
been collected (some examples will be given)
4. PK-QTc Evaluation of Ranolazine (Ranexa)
A Comprehensive Database Planned
Developed by CV Therapeutics (now Gilead) for the
symptomatic treatment of angina
– Cardiac drug that has multiple electrophysiologic effects
and an uncertain MOA, but not an anti-arrhythmic
All ECGs in CVT-sponsored studies read by a
central core ECG laboratory
Population QTc analysis of data from 15 studies
– 15,819 QTc-plasma concentration pairs
– All observations at steady state
CV Therapeutics and FDA agreed that ranolazine
prolonged QTc but patient risk was different
5. Assessment of QTc Effects of Ranolazine
Infusion to Intolerability Study
15000
31 subjects: 16 male, 15 female
5137 ECGs (3355 on ranolazine)
Target [RAN], ng/mL
Placebo (single-blind, all subjects)
Ranolazine (double-blind)
10000
5000
Vitals
PK
ECG
0
-24 0 24 48 72 96 120 -24 0 24 48 72 96 120 -24 0 24 48 72 96 120
Time, hr
Ranolazine n = 22 Ranolazine n = 22 Ranolazine n = 7
Placebo n = 6 Placebo n = 6 Placebo n = 3
6. Ranolazine Concentration vs. ∆QTc
Infusion to Intolerability Study
100 Slope = 2.29 msec per 1000 ng/mL (R2 = 0.20)
80
ΔQTc vs averaged baseline, msec
60
40
20
0
-20 The target concentration of
15,000 ng/mL could not be
-40 reached due to dizziness,
nausea, postural hypotension,
-60 diplopia, somnolence, syncope,
50% 95% Max and paresthesia.
-80
-100
0 2000 4000 6000 8000 10000 12000
Plasma ranolazine concentration, ng/mL
Individually optimized regressions of mean RR intervals and median QT intervals.
Percentiles are peak concentrations on 1000 mg bid in CVT 3031 and CVT 3033 shown for comparison.
8. Summary—Ranolazine and DQTc
The QTc effect of ranolazine is well characterized
– At plasma concentrations exceeding tolerability
– Remains linear at 2.4 msec per 1000 ng/mL
The slope of the ranolazine vs DQTc relationship was
not altered by important covariates:
– Heart rate – Heart failure – Age
– Gender – Diuretics – Anti-anginals
– This is a different profile from drugs known to cause TdP
Intolerability limits exposure to concentrations
associated with larger QTc increases
Approved by FDA and EMA
9. FDA’s Analysis of YOUR PKQT Data
Excerpted from the FDA Reviewer’s comments for the Ranolazine NDA
11. Use of a Phase I/II PK-QTc Dataset
Shashank Rohatagi et al. ACoP 2008 . ROLE OF MODELING AND SIMULATION IN EVALUATING THE
QTc PROLONGATION POTENTIAL OF DRUGS
Model based on Phase I/IIa Data Results from TQT Study
Conclusions:
1. Negative TQT study results with the anti-diabetic drug confirmed negative
simulation results from phase I/II C-QT models.
2. C-QT modeling should be implemented as a standard part of modeling and
simulation at different phases of drug development and used in conjunction with
other data that influence the need and/or the timing of a TQT study.
12. First-in-Human Near Thorough QT Study
Malik M. et al. J Clin Pharm. Aug 29, 2008.
Comparison to Completed TQT: A thorough QT study was completed after the studies
used to build the PK and E-R models. The TQT study was negative, indicating
agreement with the C-QT model.
13. First-in-Human Near Thorough QT Study
Malik M. et al. J Clin Pharm. Aug 29, 2008.
The linear regression model predicts a mean 0.6-millisecond QTc interval
prolongation per every 1000-ng/mL increase in drug concentration
15. FIH Study Conclusions
Malik M. et al. J Clin Pharm. Aug 29, 2008.
When 2 cohorts of the lowest, middle, and
highest doses were pooled (12 subjects per
active Tx group), the spreads of placebo-
corrected ΔΔQTc values were within the
regulatory requirements (single-sided 95%
confidence interval <10 milliseconds) at all time
points.
The ECG design of the FIH study provided data of
regulatory acceptable accuracy at a small fraction
of the cost of a full thorough QT study.
No disclosure if the data were accepted by FDA
16. Using PK-PD Modeling when a TQT
Study is Not Feasible or Ethical
Most biologics, due to dosing considerations
(max dose, half-life, etc…), MOA and potential
side effect profile
When you can’t use healthy subjects
– Toxicity : Droperidol—small molecule anti-emetic
– Most anti-cancer agents, particularly cytotoxics
• Example—Erlotinib (Tarceva®, Genentech/OSI)
– Started TQT but first 6 subjects developed severe facial
rash at clinical dose so stopped the study
– Designed PK-QT sub-study within the Phase 3 program at a
couple of academic, high enrolling sites with capabilities of
doing ―intensive PK‖ and QTc recording—FDA accepted
17. Droperidol Study #1: PK and QTc
Assessment of Single IV
Concentration-QT Study of 3 IV bolus doses (0.625 mg, 2.5 mg,
and 5 mg) of droperidol were studied in a 4 period, single-blind,
placebo-controlled, crossover trial in healthy subjects.
8 subjects were enrolled and exposed to one or more doses for a
total of 15 exposures
Study was stopped because of moderate to severe
neuropsychiatric side effects experienced by the volunteers.
Trend toward a dose dependent increase in the mean maximal
QTc interval change from baseline (placebo subtracted) of 1, 13,
and 30 milliseconds on the 3 doses respectively.
Outlier QTc changes of 77 and 79 msec on 2.5 & 5 mg
M.Desai1, A.Pinto2, A.Adigun2, J.Hilligoss2, S.H.Haidar1, N.Chang1, B.Rappaport1, S.M.Huang1,
J.C.Gorski2, S.D.Hall2, 1CDER, FDA, Rockville, MD, 2Indiana University, Indianapolis, IN
18. Droperidol Study #2: PK-QTc of Single IV Doses
of 1 mg Droperidol and 4 mg Ondansetron
Charbit B. et al. Anesthesiology 2008; 109:206–12
A crossover study of 16 healthy volunteers. The linear regression was significant with
droperidol (r =0.34, P=0.005) but not with ondansetron (r =0.16, P=0.26). Continuous
lines represent the linear regression with the 95% prediction band.
19. Final Thoughts
Conc-QTc Modeling is an important tool in the
clinical development plan within ICH E14
More examples of Conc-QTc modeling of Phase I
and II data accurately predicting the results from
TQT studies will lead to greater regulatory
acceptance of these efforts
Conc-QTc data collection requires careful
planning early in clinical development to make the
most of your clinical trials and to understand your
ECG risk early
Ultimate goal is to not have to do the TQT study,
which IS possible but you need to be prepared