The document discusses pharmacometrics and provides examples of its applications in drug development and clinical trials. It begins with definitions of pharmacometrics and related terms. It then provides examples of how pharmacometric modeling and simulation have been used to:
- Support pediatric drug approvals without the need for separate clinical trials by linking exposure to response between adult and pediatric patients.
- Optimize drug doses in clinical trials and make dosing recommendations for specific patient populations.
- Simulate clinical trials to determine trial designs and evaluate outcomes.
Definition and scope of Pharmacoepidemiology ABUBAKRANSARI2
In these slides I shared the information of definition and scope of pharmacoepidemiology. Types of studies - cohort studies, cross-sectional studies etc.
Spontenous adr reporting in india
PASSIVE survillence system, data assement
data aciqsition, data interpretation, what all information required in ADR form, WHEN TO REPORT
BLUE CARD,YELLOW CARD, WHO CODES
Definition and scope of Pharmacoepidemiology ABUBAKRANSARI2
In these slides I shared the information of definition and scope of pharmacoepidemiology. Types of studies - cohort studies, cross-sectional studies etc.
Spontenous adr reporting in india
PASSIVE survillence system, data assement
data aciqsition, data interpretation, what all information required in ADR form, WHEN TO REPORT
BLUE CARD,YELLOW CARD, WHO CODES
adaptive methods are doing with feedback in population pharmacokinetics---- clinical pharmacokinetics and therapeutic drug monitoring-- fifth pharm D notes
The safety monitoring in a clinical trail accompanies by common practices in safety monitoring, communicating safety information among stakeholders in a clinical trail.
Quality Use of Medicines means:
• Selecting management options wisely by:
Considering the place of medicines in treating illness and maintaining health, and
recognising that there may be better ways than medicine to manage many disorders.
• Choosing suitable medicines if a medicine is considered necessary so that the best available option is selected by taking into account:
- the individual
- the clinical condition
- risks and benefits
- dosage and length of treatment
- any co-existing conditions
- other therapies
- monitoring considerations
- costs for the individual, the community and the health system as a whole.
conversion from INTRAVENOUS TO ORAL DOSING----- design of dosage regimenpavithra vinayak
conversion from INTRAVENOUS TO ORAL DOSING----- TYPES OF IV TO PO THERAPY CONVERSIONS: MEDICATIONS INCLUDED IN AN IV TO PO CONVERSION PROGRAM: SELECTION OF PATIENTS FOR IV TO PO THERAPY CONVERSION: design of dosage regimen--clinical pharmacokinetics and therapeutic drug monitoring-- fifth pharm D notes
THIS SLIDE GIVES AN INSIGHT TO THE DIFFERENT METHODS THAT COULD BE USED FOR THE DOSAGE ADJUSTMENT IN PATIENTS WITH RENAL DISEASE.
RENAL FUNCTION OF THE PATIENT IS ASSESSED TO DETERMINE THE DOSAGE ADJUSTMENT
Bayesian theory in population pharmacokinetics--
1) INTRODUCTION TO BAYESIAN THEORY
2)BAYESIAN PROBABILITY TO DOSING OF DRUGS
3)APPLICATIONS AND USES OF BAYESIAN THEORY IN APPLIED PHARMACOKINETICS:
therapeutic drug monitoring and clinical pharmacokinetics-fifth pharm d notes
breif notes on what is pharmacoepidemiology, why do we need pharmacoepidemiology, whats is its aim and its main applications, advantages and disadvantages
detection methods of Adverse drug reactions, postal survey method, Reporting of Adverse drug reactions, Preventability assessment, predictability assessments
Therapeutic drug monitoring (TDM) of drugs used in seizure disordersAbel C. Mathew
Therapeutic drug monitoring (TDM) of drugs used in seizure disorders- Phenytoin, Valproic acid, Carbamazepine are major drugs used in epilepsy disorders. These drug need TDM to ensure their proper usage.
The presentation gives you a bird eye's view regarding basics of PK-PD modeling, its applications, types, limitations and various softwares used for the same.
adaptive methods are doing with feedback in population pharmacokinetics---- clinical pharmacokinetics and therapeutic drug monitoring-- fifth pharm D notes
The safety monitoring in a clinical trail accompanies by common practices in safety monitoring, communicating safety information among stakeholders in a clinical trail.
Quality Use of Medicines means:
• Selecting management options wisely by:
Considering the place of medicines in treating illness and maintaining health, and
recognising that there may be better ways than medicine to manage many disorders.
• Choosing suitable medicines if a medicine is considered necessary so that the best available option is selected by taking into account:
- the individual
- the clinical condition
- risks and benefits
- dosage and length of treatment
- any co-existing conditions
- other therapies
- monitoring considerations
- costs for the individual, the community and the health system as a whole.
conversion from INTRAVENOUS TO ORAL DOSING----- design of dosage regimenpavithra vinayak
conversion from INTRAVENOUS TO ORAL DOSING----- TYPES OF IV TO PO THERAPY CONVERSIONS: MEDICATIONS INCLUDED IN AN IV TO PO CONVERSION PROGRAM: SELECTION OF PATIENTS FOR IV TO PO THERAPY CONVERSION: design of dosage regimen--clinical pharmacokinetics and therapeutic drug monitoring-- fifth pharm D notes
THIS SLIDE GIVES AN INSIGHT TO THE DIFFERENT METHODS THAT COULD BE USED FOR THE DOSAGE ADJUSTMENT IN PATIENTS WITH RENAL DISEASE.
RENAL FUNCTION OF THE PATIENT IS ASSESSED TO DETERMINE THE DOSAGE ADJUSTMENT
Bayesian theory in population pharmacokinetics--
1) INTRODUCTION TO BAYESIAN THEORY
2)BAYESIAN PROBABILITY TO DOSING OF DRUGS
3)APPLICATIONS AND USES OF BAYESIAN THEORY IN APPLIED PHARMACOKINETICS:
therapeutic drug monitoring and clinical pharmacokinetics-fifth pharm d notes
breif notes on what is pharmacoepidemiology, why do we need pharmacoepidemiology, whats is its aim and its main applications, advantages and disadvantages
detection methods of Adverse drug reactions, postal survey method, Reporting of Adverse drug reactions, Preventability assessment, predictability assessments
Therapeutic drug monitoring (TDM) of drugs used in seizure disordersAbel C. Mathew
Therapeutic drug monitoring (TDM) of drugs used in seizure disorders- Phenytoin, Valproic acid, Carbamazepine are major drugs used in epilepsy disorders. These drug need TDM to ensure their proper usage.
The presentation gives you a bird eye's view regarding basics of PK-PD modeling, its applications, types, limitations and various softwares used for the same.
Lecture 7 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University.
Pharmacoeconomics is a branch of health economics which compares the value of one drug or a drug therapy to another.
By understanding the principles, methods, and application of pharmacoeconomics, healthcare professionals will be prepared to make better decisions regarding the use of pharmaceutical products and services.
UPDATED-Early Phase Drug Developmetn and Population PK and Its' ValueE. Dennis Bashaw
Presentation Given at Regional AAPS DDDI Meeting in Baltimore. Similar to previous talks BUT updated to include a discussion of BIA 10-2474 and extended discussion of risk
The dream of any physician and consequently every patient is to receive the right treatment in the right time with cost effectiveness. To achieve this goal, the 3 pillars: evidence based medicine, clinical research innovation & resources utilization should be integrated efficiently.
In this presentation, I'll try to comprehensively review the following:
1- How are we used to perform clinical trials in Oncology?
2- Does it fits in today’s needs?
3- Integration of biology knowledge in shaping drug development
4- New Clinical trial designs “Can they offer solution for accelerating drug development?”
5- The supporting infrastructure role in clinical trial execution
Clinical Research Statistics for Non-StatisticiansBrook White, PMP
Through real-world examples, this presentation teaches strategies for choosing appropriate outcome measures, methods for analysis and randomization, and sample sizes as well as tips for collecting the right data to answer your scientific questions.
Big Data and Genomic Medicine by Corey NislowKnome_Inc
View the webinar at: http://www.knome.com/webinar-big-data-genomic-medicine. This presentation covers an overview of genomic medicine, requirements and challenges of next-generation sequencing, bottlenecks to broader healthcare adoption, and why “we want to sequence everyone.”
Clinical Trial Simulation to Evaluate the Pharmacokinetics of an Abuse-Deterr...Loan Pham
A CTS was performed to estimate the sample size and optimal plasma sampling times that sufficiently characterize the PK parameters (CL, Vd) from a single dose of an abuse-deterrent (AD) opioid in pediatric subjects.
Population pharmacokinetics is the study of the sources and correlates of variability in drug concentrations among individuals who are the target patient population receiving clinically relevant doses of a drug of interest
2015 04-13 Pharma Nutrition 2015 Philadelphia Alain van GoolAlain van Gool
Keynote lecture at the Pharma-Nutrition 2015 conference, outline global paradigm shifts and activities in pharma, personalized healthcare and pharmanutrition combination therapies.
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
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
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.
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.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
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
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
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
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
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.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
2. “...The quick inference, the subtle trap, the clever forecast of
coming events, the triumphant indication of bold theories —
are these not the pride and the justification of our life’s work?”
Sherlock Holmes in `The Valley of Fear’ (Sir Arthur Conan Doyle)
2
3. INFERENCES AND FORECASTS
• Pharmacometrics
Google search – 1,19,000 results
Pubmed search - 162 items
• Google search for:
Prafull – 5,47,000 results
Animesh – 7,66,000 results
Are the presenters more popular than the topic ?
• Pubmed search
Prafull – 2 items
Animesh – 39 items
NOW ?
3
4. •Four limbs
•One tail
•Coarse skin
•One trunk
•Two ivory tusks
May or may not be an Elephant
Previous data:
Every elephant has a trunk and ivory tusks
Conclusion:
•The animal is definitely an elephant
•Chances of getting killed by poachers are high
4
6. DRUG DEVELOPMENT PROCESS
Approx $1.8 Billion
(How to improve R&D productivity: The pharmaceutical industry’s grand challenge . Nature Reviews:Drug
Discovery 2010;9:203-14)
The Food and Drug Administration (FDA) has expressed its concern in Challenge and
Opportunity on the Critical Path to New Products published in March of 2004
6
7. DRUG APPROVALS PER YEAR
7
Malorye Allison
Nature Biotechnology 30,
41–49 (2012)
doi:10.1038/nbt.2083
11. PHARMACOMETRICS
DEFINITION:
Pharmacometrics is the science of developing and applying mathematical and
statistical methods to characterize, understand, and predict a drug’s pharmacokinetic,
pharmacodynamic, and biomarker–outcomes behavior1
FDA DEFINITION
Pharmacometrics is an emerging science defined as the science that quantifies drug,
disease and trial information to aid efficient drug development and/or regulatory
decisions
1. P. J. Williams, A. Desai, and E. I. Ette, in The Role of Pharmacometrics in Cardiovas- cular Drug Development, M. K. Pugsley
(Ed.). Humana Press, Totowa, NJ, 2003, pp. 365–387.
11
13. HISTORY AND DEVELOPMENT
• Peck- Ludden 87-95
Drug concentration development paradigm
Individual PK forecasting & individualized Rx
Population PK/PD applications
Pharmacometrics derived evidence of efficacy/safety (e.g., Phase 2b-3)
Randomized concentration-controlled trial
13
14. 1997
• Population PK guidance
2001
• End of Phase 2a Meeting idea emerged CDDS meeting 5
2002
• Clinical pharmacology subcommittee emphasizing
pharmacometrics solutions
• Drug approval decision based on PM analysis
2003
• Exposure-Response guidance
2007
• Disease model & trial design started (Parkinson’s disease)
• QT trial design & concentration-response analysis
2011
• Strategic plan emphasizing PM
• Centralized PM Data warehouse-Software environment
Lesko -Woodcock-
Galson –Murphy
95-present
14
17. CALCULATION OF POSTERIOR
PROBABILITY FROM PRIOR
PROBABILITY
• Suppose someone told you he had a nice conversation with someone on the
train
• Assuming women constitute half of the population the probability of the event
that the conversation was held with a woman P(W)= 0.5
• Then we come to know that the person had long hair
• Suppose it is also known that 75% of women have long hair and 25% of men
have long hair
18
18. CALCULATION OF POSTERIOR
PROBABILITY FROM PRIOR
PROBABILITY
Now our posterior probability of the person being a woman given the fact that the
person had long hair is
or
19
19. 20
A SIMPLE EXAMPLE
• Unknown parameter (): long-term systolic blood
pressure (SBP) of one particular 60-year-old female
• 4 measurements with a mean and a standard
deviation =5
• Survey of the same population (60-year-old female):
mean SBP =120 and standard deviation =10
130Y
21. 11/13/2008NONMEM Estimation Methods
22
ESTIMATION OF
• Frequentist
• Point estimate:
• Interval estimate (95%CI)
• Bayesian
• Posterior distribution P(|Y)
• Posterior mean
• 95% credible interval
130ˆ Y
5.2*96.113096.1
n
Y
4.129|ˆ Y
4.2*96.14.129
22. 23
PRIOR, LIKELIHOOD AND POSTERIOR
xp
pdens
80 100 120 140 160
0.00.050.100.15
Population Distribution
(prior)
Individual data
(likelihood)
Individual parameter
(posterior)
Long-term systolic blood pressure (SBP) of 60-year-old woman
23. BAYESIAN STATISTICS AND
PHARMACOMETRICS
• An important fact about a pharmacometrics based experiment is that
the design of any experiment is conditioned upon the results and
understanding of previous experiments.
• The process is inherently Bayesian.
24
24. 25
DEFINITION OF MODELING
Mathematical (conceptual) modeling is describing a physical phenomenon
by logical principles characterized with quantitative relationships, e.g.,
formulas, whose parameters may be measured (or experimentally
determined)
http://www.hawcc.hawaii.edu/math/Courses/Math100/Chapter0/Glossary/Glossary.htm
25. 26
USES OF MODELS
Yates FE (1975) On the mathematical modeling of biological systems: a qualified “pro”, in Physiological Adaptation to
the Environment (Vernberg FJ ed), Intext Educational Publishers, New York.
1. Conceptualize the system
2. Codify current facts
3. Test competing hypotheses
4. Identify controlling factors
5. Estimate inaccessible system variables
6. Predict system response under new conditions
26. DISEASE MODEL
• Mathematical models to
i. describe
ii. explain
iii. investigate
iv. Predict
the changes in disease status as a function of time
• . It incorporates
• functions of natural disease progression
• Placebo effect
• Drug action which reflects the effect of a drug on disease status
27
27. POPULATION PHARMACOKINETIC
AND PHARMACODYNAMIC
MODELING
Population modeling involves the analysis of data from a group
(population) of individuals, with all their data analyzed
simultaneously to provide information about the variability of the
model's parameters.
28
28. OXCARBAZEPINE
• Adjunct and monotherapy in adult patients and as adjunct therapy in
pediatric patients with partial seizures
• Exposure-seizure frequency data collected from adult and pediatric patients
submitted originally was subjected to qualitative analysis and to build an
exposure-response model to test:
whether placebo responses in adult and pediatric patients were similar
whether the exposure-response relationships in the 2 populations were similar
Derive reasonable dosing recommendations for monotherapy in pediatric patients
• Mixed-effects modeling indicated no important differences in the placebo and
drug effects between adults and pediatric pts.
Oxcarbazepine monotherapy in pediatric patients was approved without the need
for specific controlled clinical trials
(Bhattaram VA, Booth BP, Ramchandani RP. The AAPS Journal 2005; 7 (3))
29
29. CLINICAL TRIAL SIMULATION
• Simulation of a clinical trial can provide a data set that will resemble the
results of an actual trial.
• Multiple replications of a clinical trial simulation can be used to make
statistical inferences
• Estimate the power of the trial
• Predicting p-value
• Estimate the expected % of the population that should fall within a
predefined therapeutic range
30
30. NESIRITIDE
• Drug nesiritide for treatment of acute decompensated congestive heart failure
• PD marker: Pulmonary capillary wedge pressure (PCWP)
• Nesiritide reduced PCWP but also reduced SBP.
• Desired effects cannot be achieved without undesired effects, such as hypotension
April 1999, FDA issued a nonapprovable letter to the sponsor
Exposure and response data from the original submission were modeled and model was used to
explore various alternative dosing scenarios
31
31. 2 mg/kg followed by 0.01
mg/min/kg infusion offered a
reasonable benefit-risk profile.
This dosing regimen was selected
for additional investigation in the
Vasodilation in the Management of
Acute CHF (VMAC) trial.
The results obtained from the
VMAC trial and the simulations are
in close agreement with those
observed
NESIRITIDE
May 2001, FDA approved nesiritide for CHF
Publication Committee for the VMAC Investigators.
JAMA. 2002;287:1531-1540.
32
32. 33
TOOLS FOR MODELING AND SIMULATION
• NONMEM (UCSF, Globomax)
• SAS (SAS Institute Inc)
• Splus (Insightful Corporation) or R (Free)
• WinBUGS (MRC Biostatistics, Free)
• ADAPT II (USC, Free)
• WinNonLin/WinNonMix (Pharsight)
• Trial Simulator (Pharsight)
34. APPLICATIONS OF PHARMACOKINETICS IN
CLINICAL TRIALS
• Dose determination in pediatric trials
• Optimizing dose in clinical trials (CT)
• Faster drug development
• Drug approvals without CT
• Better trial designs
• Risk reduction in CT
• Dose finding in adults
• Strengthening pharmacogenomics
• Evolving new strategies
35
35. TRIALS IN CHILDREN
Trials in adults
• Based on mortality benefits
• Large sample size
• Homogenous population
• Ethical issues
Trials in children
• Mainly to support dosing
recommendations
• Heterogeneous population
• Smaller samples and sample
sizes
Do more with less
36
36. TIPRANAVIR
• Tipranavir capsule, was approved as an HIV-1 protease inhibitor in adult patients
• seeking an approval of APTIVUS oral solution (OS) and capsule for HIVinfected
pediatrics 2 to 18 years of age
• 48-week, open-label, parallel, randomized clinical trial with 2 doses of TPV OS with
ritonavir (RTV).
290 + 115 mg/m2 (BSA adjusted adult dose) 375 + 150 (30% higher than lower dose
Matched exposure with
adult dose
Increased virological success
But:
•Better efficacy only in pts with higher no of mutations
•And Age of the patient directly correlates with no of mutations
•Higher dose for children > 6ys
•Lower dose for children < 6 yrs
•(Salazar JC, Cahn P, Yogev R, et al. AIDS. 2008;22:1789-1798
•US Food and Drug Administration. Pediatric drug development
2009. http://www.fda.gov/cder/pediatric/index.htm)
37
37. TIPRANAVIR Contd……
•Higher dose for children > 6ys
•Lower dose for children < 6 yrs
But:
In adult patients TPV is indicated for treatment experienced pts who are
likely to have more mutations.
In paed population too, target pt group is likely to have more mutations
Higher dose range recommended for all children
38
38. TIPRANAVIR Contd……
Higher dose range recommended for all children
But:
Pharmacokinetics of TPV are a function of body wt and not BSA or age
•Simulations were done for weight based dosing in place of BSA adjusted dosing
•12/5 mg/kg and 14/6 mg/kg were new decided as lower and higher doses.
TPV/RTV in the dose of 14/6 mg/kg approved for children
For adults too, recommended dose was increased to 375/150 mg/m2
39
39. FENOLDAPAM
• Systemic and renal vasodilator, approved in adults for in-hospital, short-term
management of severe hypertension
• Adult dose: 0.01 to 1.6 μg/kg/min
• Seeking an approval of fenoldopam for the pediatric population (from 1 month to
12 years of age) for the same indication.
• The sponsor studied doses of 0.05, 0.2, 0.8, and 3.2 μg/kg/min in pediatrics
Doses upto 0.8 mcg/kg/min
were approved
(Hammer GB, Verghese ST, Drover DR, Yaster M, Tobin JR. . BMC
Anesthesiol. 2008;8:6).
40
40. CANDESARTAN• Candesartan cilexetil, an ARB,
approved for the treatment of
hypertension and heart failure in
adults.
• Two 4-week dose-ranging safety
and efficacy studies were conducted
in hypertensive pediatric
participants
• 2 age groups (6 to <17 years and 1
to <6 years) were studied
separately
1 < 6 yrs 6 yrs – 17 yrs
Beneficial Not Beneficial
Placebo corrected versus placebo anchored analysis
US Food and Drug Administration. Review.
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM189129.pdf
41
41. FLUCONAZOLE• Triazole antifungal drug that is used to treat
invasive candidiasis in neonates in intensive
care
• Pharmacokinetic study to assess the dose-
exposure relationship in neonatal infants who
were 23 to 40 weeks gestational age
• 55 infants who contributed 357 plasma samples;
60% were from specified study sample times,
40% were scavenged samples
• Investigators developed a detailed population
model that showed the influence of a number of
clinical covariates on differences in
pharmacokinetics
(Wade KC, Wu D, Kaufman DA, et al. Population pharmacokinetics of fluconazole in young infants. Antimicrob
Agents Chemother. 2008;52:4043-4049)
Dose needed for a 24-week-old infant is approximately 67% lower on an mg/kg/d
basis than that necessary to treat a 32-week-old or a 40-week-old infant
42
42. SOTALOL
• Approved for ventricular and supraventricular tachycardia in adults
• sponsor conducted 2 clinical trials to investigate the antiarrhythmic potential
in pediatrics ages 1 month to 12 years
• Dosing recommendation: 30 mg/m2 three times daily as a starting dose with
subsequent titration to a maximum of 60 mg/m2.
• The PD effects of sotalol in pediatrics were similar to those in adults for a
given exposure. Hence, the exposure in the adults was a reasonable target
in pediatrics
• Clearance of sotalol increases until the patient reaches 2 years of age
independent of body-size; after 2 yrs it depends only on body size.
43
43. • FDA proposed a dose in
patients <2 years of age that
included an age factor
• The dosing recommendations
for sotalol in pediatrics aged 1
month to 12 years old were
incorporated in the labeling
• modeling efforts led to the
specific dosing instructions,
which were not directly
studied in trials, in patients <2
years of age.
SOTALOL
(Shi J, Ludden TM, Melikian AP, Gastonguay MR, Hinderling
PH. J Pharmacokinet Pharmacodyn. 2001;28:555-575).
44
44. LEVOFLOXACIN
• Approved by FDA in 2008 as treatment for children following inhalational exposure
to anthrax.
• Pharmacokinetic (PK) data from 90 pediatric patients receiving 7 mg/kg and two
studies of 47 healthy adults receiving 500 and 750 mg/kg levofloxacin were used
for the pharmacometric analyses.
• Body weight:covariate for levofloxacin clearance and the volume of distribution
• Clearance: reduced in pediatric patients under 2 years of age due to immature
renal function
• Different dosing regimens were simulated to match adult exposure
• Dose of 8 mg/kg twice a day was found to match the exposure of the dose
approved for adults
Indication added without actually conducting clinical trial
(Li F, Nandy P, Chien S, Noel GJ, Tornoe CW. Antimicrob Agents Chemother. 2010 Jan;54(1):375-9)
45
46. PK OF DABIGATRAN
• Dabigatran etexilate is the orally bioavailable pro-drug of dabigatran, a direct
thrombin inhibitor
• Data from eight clinical studies in healthy volunteers and patients population
pharmacokinetic (PK) and pharmacodynamic (PD) models were developed
to investigate whether the PK and PD of dabigatran differ across different
populations
• Renal function was the only covariate shown to have a clinically relevant
impact on dabigatran exposure
• PK of dabigatran is sufficiently consistent to allow extrapolation of data
generated in healthy volunteers to patients with AF or undergoing OS.
(Dansirikul C, Lehr T, Liesenfeld KH, Haertter S, Staab A. Thromb Haemost. 2012 Apr;107(4):775-85)
47
47. DABIGATRAN HEMODIALYSIS
• Hemodialysis a useful method of decreasing dabigatran plasma levels.
• Seven patients with ESRD were investigated in an open-label, fixed-
sequence, two-period comparison trial
• A population pharmacokinetic model was developed to fit the data and then
used for various simulations
• Dialysis duration had the strongest impact on dabigatran plasma
concentration
• Dialysis settings such as filter properties or flow rates had only minor effects
• The final model was successfully evaluated through the prediction of plasma
concentrations from a case report undergoing dialysis.
(Liesenfeld KH, Staab A, Härtter S, Formella S, Clemens A, Lehr T. Clin Pharmacokinet. 2013 Mar 26. [Epub])
48
48. PHARMACO –
GENOMICS AND METRICS
• Patients from a pharmacokinetic sub study, were reconsented and reenrolled
into a clinical trial for genotyping analysis
• 198 single nucleotide polymorphisms were genotyped
• 1260 nevirapine plasma concentrations obtained from 271 genotyped
patients
• Nevirapine clearance was 19.4% reduced in Asian/Black patients, compared
with Caucasian/Hispanic patients
• By integration of high-throughput genotyping data into a pharmacometric
analysis of nevirapine, the impact of the CYP2B6 516G>T polymorphism on
nevirapine's exposure was confirmed and quantified
(Lehr T, Yuan J, Hall D, Zimdahl-Gelling H. Pharmacogenet Genomics. 2011 Nov;21(11):721-30)
49
49. SWOT ANALYSIS
Strength:
quantitatively explore relationships among
different disease targets, quantify risk and
benefits
• Platform for communication for decision
makers
• Portability across modelers and
regulatory agencies
Threats: Protection of intellectual
property
Lack of regulatory guidelines
Lack of data warehouse and IT
infrastucture
Opportunities:
Engage project team at discovery stage,
Integrate knowledge across phases
• Create a shared vision
• Develop standard definitions
Weakness:
Shortage of trained experienced
leaders
• No shared strategic vision
• No standard process and definition
• No defined roles, responsibilities
50
Model-Based Drug Development : Strengths, Weaknesses, Opportunities, and Threats for Broad Application of Pharmacometrics in Drug Development Pharmacol 2010 50: 31S
Jeffrey D. Wetherington, Marc Pfister, Christopher Banfield, Julie A. Stone, Rajesh Krishna, Sandy Allerheiligen
51. The demand for scientists with pharmacometrics skills has risen
substantially. Likewise, the salary garnered by those with these
skills appears to be surpassing their counterparts without such
backgrounds
(Barrett JS, Fossler MJ, Cadieu JS. J Clin Pharm 2008;Volume 48 (5): 632–649)
52
53. SUGGESTED READING
• Pharmacometrics: The Science of Quantitative Pharmacology Edited by Ene
I. Ette and Paul J. Williams John Wiley & Sons, Inc
• Pharmacometrics 2020DOI: 10.1177/0091270010376977 J Clin Pharmacol
2010 50: 151S Jogarao V. S. Gobburu
• Exposure-Response Modeling of Darbepoetin Alfa in Anemic Patients With
Chronic Kidney Disease not Receiving DialysisDOI: 0.1177/0091270010377201
J Clin Pharmacol 2010 50: 75S Sameer Doshi, Andrew Chow and Juan José
Pérez Ruixo
54
54. SUGGESTED READING
• Pharmacometrics as a Discipline Is Entering the ''Industrialization'' Phase:
Standards, Automation, Knowledge Sharing, and Training Are Critical for
Future Success J Clin Pharmacol 2010 50: 9S R. Gastonguay, Bernd Meibohm
and Hartmut Derendorf
• Model-Based Drug Development : Strengths, Weaknesses, Opportunities, and
Threats for Broad Application of Pharmacometrics in Drug DevelopmentJ Clin
Pharmacol 2010 50: 31S Dennis M. GraselaJ Clin Pharmacol 2010 50: 31S
Jeffrey D. Wetherington, Marc Pfister, Christopher Banfield, Julie A. Stone,
Rajesh Krishna, Sandy Allerheiligen
55