1) The document discusses mechanistic oral absorption modeling (MAM) and its potential use in predicting food and drug effects.
2) It describes a case study where MAM was used retrospectively to predict the effect of acid reducing agents (ARAs) like omeprazole on the drug erlotinib. The model was able to reasonably simulate clinical observations.
3) Efforts like a cross-industry working group aim to build confidence in MAM through evaluating predictions against clinical data using consistent methods and criteria. Regulatory acceptance of MAM could help streamline development by reducing unnecessary studies.
The Relationship Between Quality of Care and Choice of Clinical Computing System: Retrospective Analysis of Family Practice Performance Under the UK Quality and Outcomes Framework
The Relationship Between Quality of Care and Choice of Clinical Computing System: Retrospective Analysis of Family Practice Performance Under the UK Quality and Outcomes Framework
Safety is the prime attention of regulatory bodies as it is the critical factor which can destroy even the humankind. Quality system like GLP has a lot tom play in the field of safety
assessments to reach its goal. There are various toxicity studies for assessing the degree of its toxicity. Academic research and peer reviewed journals has their own pitfalls as they could not
monitor or inspect the studies which has been conducted. This presentation speak about the Importance of safety assessment, various studies to evaluate the safety and Importance of GLP in safety assessment.
MicroGuide app, pop up uni, 1pm, 3 september 2015NHS England
Expo is the most significant annual health and social care event in the calendar, uniting more NHS and care leaders, commissioners, clinicians, voluntary sector partners, innovators and media than any other health and care event.
Expo 15 returned to Manchester and was hosted once again by NHS England. Around 5000 people a day from health and care, the voluntary sector, local government, and industry joined together at Manchester Central Convention Centre for two packed days of speakers, workshops, exhibitions and professional development.
This year, Expo was more relevant and engaging than ever before, happening within the first 100 days of the new Government, and almost 12 months after the publication of the NHS Five Year Forward View. It was also a great opportunity to check on and learn from the progress of Greater Manchester as the area prepares to take over a £6 billion devolved health and social care budget, pledging to integrate hospital, community, primary and social care and vastly improve health and well-being.
More information is available online: www.expo.nhs.uk
Quality control during processing and storageJuhiMishra16
describes about microbiological quality criteria and about indicator organisms and their isolation. lays emphasis on GMP and HACCP AND ITS PRINCIPLES. also describes about risk analysis
Accelerating the translation of medical research - 27 JuneInnovation Agency
Slides from the event focusing on translational research in Liverpool and North of England and why companies are establishing and growing operations in the region.
Good Laboratory Practices: General Provisions, Organization and Personnel, Facilities,
Equipment, Testing Facilities Operation, Test and Control Articles, Protocol for Conduct
of a Nonclinical Laboratory Study, Records and Reports, Disqualification of Testing
Facilities
Safety is the prime attention of regulatory bodies as it is the critical factor which can destroy even the humankind. Quality system like GLP has a lot tom play in the field of safety
assessments to reach its goal. There are various toxicity studies for assessing the degree of its toxicity. Academic research and peer reviewed journals has their own pitfalls as they could not
monitor or inspect the studies which has been conducted. This presentation speak about the Importance of safety assessment, various studies to evaluate the safety and Importance of GLP in safety assessment.
MicroGuide app, pop up uni, 1pm, 3 september 2015NHS England
Expo is the most significant annual health and social care event in the calendar, uniting more NHS and care leaders, commissioners, clinicians, voluntary sector partners, innovators and media than any other health and care event.
Expo 15 returned to Manchester and was hosted once again by NHS England. Around 5000 people a day from health and care, the voluntary sector, local government, and industry joined together at Manchester Central Convention Centre for two packed days of speakers, workshops, exhibitions and professional development.
This year, Expo was more relevant and engaging than ever before, happening within the first 100 days of the new Government, and almost 12 months after the publication of the NHS Five Year Forward View. It was also a great opportunity to check on and learn from the progress of Greater Manchester as the area prepares to take over a £6 billion devolved health and social care budget, pledging to integrate hospital, community, primary and social care and vastly improve health and well-being.
More information is available online: www.expo.nhs.uk
Quality control during processing and storageJuhiMishra16
describes about microbiological quality criteria and about indicator organisms and their isolation. lays emphasis on GMP and HACCP AND ITS PRINCIPLES. also describes about risk analysis
Accelerating the translation of medical research - 27 JuneInnovation Agency
Slides from the event focusing on translational research in Liverpool and North of England and why companies are establishing and growing operations in the region.
Good Laboratory Practices: General Provisions, Organization and Personnel, Facilities,
Equipment, Testing Facilities Operation, Test and Control Articles, Protocol for Conduct
of a Nonclinical Laboratory Study, Records and Reports, Disqualification of Testing
Facilities
“EU regulatory and clinical development framework for biosimilars”
Explains the current EU experience and practices relating to the submission and approval of biosimilars
Turning up the Compen-DIAL: Rapid Test Methods for Cell & Gene TherapiesMerck Life Sciences
Watch the presentation of this webinar here: https://bit.ly/3aeCPNB
Find out how we turn up the dial on quality control testing for cell and gene therapies through rapid methods for sterility, mycoplasma, and replication competent virus. We will review the current regulatory expectations as well as the benefits and limitations that come with each method.
Two of the biggest challenges with applying traditional quality control (QC) test methods to cell and gene therapies, is time to results, due to short shelf-life, and availability of sufficient sample, due to small production volumes.
So how can these challenges be overcome while still meeting regulatory expectations?
In this webinar we will discuss and review suitable methods for rapid testing of short-life cell and gene therapies that may also help conserve limited production material. We will look at benefits, limitations, and regulatory expectations for various QC needs including current and future rapid methods for sterility, mycoplasma and replication competent virus.
In this webinar, you will learn:
• Why the shelf life of a cell or gene therapy product may impact your QC testing strategy
• Current regulatory expectations surrounding rapid methods for sterility, mycoplasma and replication competent virus
• Potential impacts of pursuing a non-optimal QC testing strategy
Turning up the Compen-DIAL: Rapid Test Methods for Cell & Gene TherapiesMilliporeSigma
Watch the presentation of this webinar here: https://bit.ly/3aeCPNB
Find out how we turn up the dial on quality control testing for cell and gene therapies through rapid methods for sterility, mycoplasma, and replication competent virus. We will review the current regulatory expectations as well as the benefits and limitations that come with each method.
Two of the biggest challenges with applying traditional quality control (QC) test methods to cell and gene therapies, is time to results, due to short shelf-life, and availability of sufficient sample, due to small production volumes.
So how can these challenges be overcome while still meeting regulatory expectations?
In this webinar we will discuss and review suitable methods for rapid testing of short-life cell and gene therapies that may also help conserve limited production material. We will look at benefits, limitations, and regulatory expectations for various QC needs including current and future rapid methods for sterility, mycoplasma and replication competent virus.
In this webinar, you will learn:
• Why the shelf life of a cell or gene therapy product may impact your QC testing strategy
• Current regulatory expectations surrounding rapid methods for sterility, mycoplasma and replication competent virus
• Potential impacts of pursuing a non-optimal QC testing strategy
An Analysis on the UV-Visible Spectrophotometry MethodAI Publications
In the pharmaceutical industry, quality control is a necessary process. Pharmaceutical medicinal products must be advertised as safe, therapeutically active formulations with predictable qualities and performance. The main aim of the study is an analysis on the UV-Visible Spectrophotometry Method. UV spectroscopy was performed on Shimadzu 1700 uv spectrometer, 1cm cell quartz cuvette. Mode was set as UV mode and Detector wavelength was kept at 231 nm and 276 nm. A simple, rapid, accurate, sensitive and cost economical methodology for simultaneous estimation and precise ultraviolet radiation methodology has been developed and valid as per ICH guidelines for simultaneous Estimation of MET and AGP in Their Combined dose form.
Gastrointestinal absorption simulation using in silico methodology; by Dr. Bh...bhupenkalita7
This PPT includes a brief introduction of in silico models for simulation of GI absorption of drugs, principles involved in the dvelopment of computational models for in silico pharmacokinetic studies related to absorption of drugs from GI tract.
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.
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
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.
- 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
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
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
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.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
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
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.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
NVBDCP.pptx Nation vector borne disease control program
Mechanistic Oral Absorption Modelling, An update on cross-industry activities
1. Mechanistic Oral Absorption Modelling
An update on cross-industry activities
Neil Parrott, Pharmaceutical Sciences,
Roche Pharma Research and Early Development, Roche Innovation Center Basel
1
Paris, April, 2019
5. Confidence in MAM : Regulators
5
AAPS webinar Sept 2017. First-In-Class Regulatory PBPK Modeling
Guidelines from both Sides of the Pond – Ping Zhao, Anna Nordmark.
https://www.pathlms.com/aaps/events/643/video_presentations/80736
“Very low confidence”
“Not scientifically there yet”.
6. Confidence in MAM : Regulators
6
“The large knowledge gaps in product, API, and physiology hinder the ability of
PBPK to prospectively predict the food effect”
48 food effect predictions
~50% within 1.25-fold
75% within 2-fold
7. Regulatory Guidance Prior to 2019
7
Food effect bioavailability studies are needed to support global filings of NDAs
8. Regulatory Guidance 2019
8
No mention of MAM
A missed opportunity to encourage this to
streamline and enhance food effect
assessments. May effectively discourage
sponsors from investing in this approach
Mentions possible consideration of BCS
category to waive FE studies specifically for
BCS1 without high first pass metabolism.
9. New from the GastroPlus User Group
9
Journal of Pharmaceutical Sciences Volume 108, Issue 1, January 2019, Pages 592-602
10. New from the GastroPlus User Group
10
• Consideration of molecule type to set level
of confidence
• Workflow with standardized inputs and a
model validation step with clinical data in
one prandial state
• Model must be validated against clinical
food effect data before prediction of food
effect (e.g., for new formulations, API
polymorphs, or change of dose)
• Mechanistic predictions of food effect
could substitute for unnecessary clinical
studies during late-stage clinical
development or life cycle management
11. PBPK Food Effect Working Group
January 2018 – Dec 2019
Chair – Arian Emami Riedmaier (AbbVie)
Co-chair – Neil Parrott (Roche)
Goals
• Assess performance of mechanistic model predictions of
food effect using a consistent strategy and input data
• Provide an industry best practice, categorizing molecules
according to prediction confidence
12. Timeline - 2019
Jan Feb Mar Apr May Jun Jul Aug Sep NovOct Dec
• Evaluate modeling
outcome and
progress
• Finalize any
outstanding
modeling work
• Compile information
on modeling success
based on criteria
Manuscript compilation and
writing
• Post-modeling
evaluation
(e.g. sensitivity
analysis)
• Reach out to
regulatory
authorities for
input
Review and submit
manuscript
13. The European Network on Understanding
Gastrointestinal Absorption-related Processes
• COST ACTION CA16205
• SPRING MEETING Sofia, 12-13 Feb 2019
• Presentations available at
https://gbiomed.kuleuven.be/english/research/
50000715/50000716/ungap
14. Predicting the Effect of Acid Reducing Agents
• pH-dependent DDI may occur in the stomach when a poorly soluble
weakly basic drug with pH dependent solubility is co-administered with an
acid reducing agent (ARA) e.g. proton pump inhibitor (PPI), histamine 2
receptor antagonist (H2RA) or antacid
• Many weakly basic compounds show reduced exposure (Cmax and AUC)
which can lead to significant impact on efficacy of these compounds
16. MAM for ARA
• Data on pH-dependent solubility can be integrated
• Measured data on the physiological changes due to ARA can be integrated
– PPIs increases fasting gastric pH from ~1.3 to ~4.5
– Postprandial gastric pH increases from ~4.5 to ~6.5
– Decreased gastric emptying rate
FastedFed
4 - 56.5 1.8
17. A Case Study
• Erlotinib EGFR inhibitor used to treat
patients with locally advanced or
metastatic non-small cell lung cancer
• Lipophilic with high permeability and
low solubility
• CYP3A4 & CYP1A2 substrate
• The effect of omeprazole and
ranitidine on erlotinib has been
studied clinically and this modelling
was done retrospectively
Parameter
logP (O/W) 2.7
pka 5.65
fu 0.046
B/P 0.55
Permeability (cm/s) caco-2 33.6x10-6 -> human Peff 4.3x10-4
Buffer solubility of
HCl salt at different
pH (mg/ml)
pH mg/mL
2.5 0.6
3.4 0.32
5 0.0145
6.5 0.0058
Biorelevant solubility
at 37°C (mg/ml)
Media start pH end pH mg/mL
FaSSIF 6.5 6.4 0.0085
FeSSIF 5 5 0.0533
18. Step 1: Disposition Model
• Mean Cp(t) for IV and PO crossover
study 150-mg tablet vs 25-mg 30
minute intravenous infusion in 20
healthy mainly female subjects
• 2 compartmental model with nonlinear
clearance fit gives best fit
• Bioavailability estimated with saturable
clearance is 59% vs 106% based on a
simple non-compartmental analysis
Vc/kg= 0.826 L/kg CV= 26%
CL2/kg= 0.150 L/h/kg CV= 54%
V2/kg= 1.138 L/kg CV= 33%
Vmax = 4.47E-4 mg/s CV= 53%
Km = 0.232 µg/mL CV= 77%
K12 = 0.182 1/h CV= 60%
K21 = 0.132 1/h CV= 63%
Tlag = 0.228 h CV= 19%
Ka = 0.731 1/h CV= 53%
F = 59.27 % CV= 19%
nonlinear model fit in PKPlus
19. Step 2: Fasted State Simulation
• Vmax and Km transferred to
the enzyme table accounting
for changed units and free
fraction in plasma
• Default model simulation over
estimates observed Cp(t)
• Reduction in %fluid colon
improves match
10% fluid in colon
25% absorption from the large intestine.
1% fluid in colon
8% absorption from the large intestine.
20. Step 3: Fasted State with/without ARA
• Stomach pH changed from 1.3 to 4.0
• Gastric transit increased from 0.25h to 0.5hWithout omeprazole
Without ranitidine
With omeprazole
With ranitidine
AUCinf omeprazole ranitidine
Observed 54% 67%
Simulated 51% 60%
Sensitivity to gastric pH
21. Role of MAM in Managing the Effect of ARA
• MAM should play a role in integrating physicochemical, in vitro and in vivo data into a
mechanistic framework which can yield a fuller understanding of pH dependent DDIs
• A bottom-up approach assumes that all relevant factors are captured in the model and that in
vitro to in vivo translation is accurate.
• Therefore verification of simulations with clinical data is recommended before application to
predict untested situations
• PBPK simulations should be used to guide study design appropriately and allow exploration
of different scenarios (e.g. staggering of dosing with regard to the two interacting drugs)
• Collaborative cross-industry efforts are need to build confidence and extend the utility of this
approach. Further work is needed to support more detailed models for physiological
changes due to different types of ARA and in different populations.
22. Conclusion
• There is wide recognition of the
potential for MAM to streamline
development of oral formulations
• Increased confidence in MAM is
needed to expand the impact
with the regulators
• Collaborative efforts are ongoing
to address this and we can
confidently expect progress in the
near future PBPK in IND/NDA submissions to US
FDA OCP from 2008 to 2017
Grimstein et al JPS 2019
23. Coming in 2019
• FDA hosted workshop to take place in
Silver Spring this September
• Physiological Based Biopharmaceutics Modeling
(PBBM) to Support Pharmaceutical Quality
• Day 1 in vitro,
• Day 2 model verification
• Day 3 case studies.
• J. Dressman, Uni Frankfurt
• Xavier Pepin, AstraZeneca
• FDA
• Sandra Suarez, Andrew Babiskin, Poonam Delvadia,
Vidula Kolhatkar, Xinyuan Zhang,
24. Acknowledgements
• Colleagues from Roche pRED Pharmaceutical Sciences
• Colleagues from the GastroPlus User Group
• Colleagues from the IQ Food Effect Working Group
24
25. Questions raised by FDA
• What are the characteristics of drugs that are susceptible to pH-dependent
DDIs? Can a stepwise approach be applied to evaluate the interaction
potential?
• When conducting pH-dependent DDI assessments:
– What are the utilities and limitations of different approaches to evaluating DDIs (e.g., in silico,
in vitro, and dedicated clinical studies, as well as population pharmacokinetic analyses)?
– What are the study design considerations (e.g., study population, choice of ARAs, dosing
regimen and administration, and pharmacokinetic sampling) for the in vivo assessments
discussed in 2a above?
– Can we extrapolate the findings from a clinical DDI study with one ARA drug (a PPI, H2
blocker, or antacid) to anticipate the DDI potential for other ARAs in the same class or in a
different class?
Editor's Notes
Roche’s diverse approach to research and early development is carried out by four organisations: Roche Pharma Research and Early Development (pRED), Genentech Research and Early Development (gRED), Chugai Pharmaceutical Co. Ltd, Japan, a member of the Roche Group, and our Diagnostics Division.
is a multidisciplinary Network of scientists aiming to advance the field of intestinal drug absorption by focussing on 4 major challenges:
, i.e. soluble under acidic pH environment but insoluble in higher pH,
ARAs are widely prescribed to reduce gastric acidity for treatment of diseases such as gastric ulcer and in oncology and many of these products are available over the counter (refs). Clinical data for several weakly basic compounds has shown reduced exposure (Cmax and AUC) and in some cases prolonged Tmax in achlorhydric subjects/patients (refs). Such reduction in exposure can lead to significant impact on efficacy of these compounds
FDA) is establishing a public docket to assist with the development of a policy or guidance document on the assessment of pH-dependent drug-drug interactions (DDIs)
Acid-reducing agents (ARAs) such as antacids, histamine H2-receptor antagonists (H2
blockers), and proton pump inhibitors (PPIs) are widely used, and many of these products are
available over the counter (Refs. 3 and 4). For a drug whose solubility is pH-dependent,
concomitant administration with an ARA may affect its absorption and systemic exposure,
potentially resulting in loss of efficacy or, in some cases, increased toxicity.
What are the characteristics of drugs that are susceptible to pH-dependent DDIs? Can a stepwise approach be applied to evaluate the interaction potential?
When conducting pH-dependent DDI assessments:
What are the utilities and limitations of different approaches to evaluating DDIs (e.g., in silico, in vitro, and dedicated clinical studies, as well as population pharmacokinetic analyses)?
What are the study design considerations (e.g., study population, choice of ARAs, dosing regimen and administration, and pharmacokinetic sampling) for the in vivo assessments discussed in 2a above?
Can we extrapolate the findings from a clinical DDI study with one ARA drug (a PPI, H2 blocker, or antacid) to anticipate the DDI potential for other ARAs in the same class or in a different class?
which increases at a pH of less than 5 due to protonation of a secondary amine
24 mainly male volunteers
PEARRL project (no.674909) PEARRLs of Wisdom Week 2019 : 10th– 14nd June 2019
Theme of Annual meeting : Model Informed Drug Development
Day 4 – 13th June 2019 - Open scientific symposium on Model Informed Drug Development
Theme: Clinical development through to pharmaceutical product lifecycle management
"Kesisoglou, Filippos" <filippos_kesisoglou@merck.com>, "Heimbach, Tycho" <tycho.heimbach@novartis.com>, Neil Miller <neil.a.miller@gsk.com>, "Richard Lloyd (richard.s.lloyd@gsk.com)" <richard.s.lloyd@gsk.com>, "Tistaert, Christophe [JRDBE]" <CTISTAER@its.jnj.com>