KD CI50 KI
KI. Emax. CE50 DE50. KB pA2. Définition. Nbr maximum de sites de liaison du médicament. Constante de dissociation à l'équilibre. Concentration de médicament.
Pharmacologie
Pharmacologie moléculaire. Pharmacologie et chimie des médicaments ; Y. Landry et ... b)? Détermination?de?l'affinité?Ligand-récepteur?KD?et?Ki.
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The Prognostic Role of CD8+ T Lymphocytes in Childhood
05-Nov-2019 Institut de Pharmacologie Moléculaire et Cellulaire CNRS ... between Ki-67 expression and poor prognosis in pediatric ACC is not consistent ...
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How chronic is polypharmacy in old age? A longitudinal nationwide
14-Mar-2019 http://openarchive.ki.se ... Universitaire de Limoges Service de Pharmacologie
Identification of Amino Acid Residues in the
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aService de Pharmacologie-Toxicologie Hôpital Dupuytren
Multi-Discipline Review
19-Jul-2019 OX2R lemborexant similarly acted as an antagonist at both receptors
How to measure and evaluate binding affinities
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Dunod
Dunod
Loyola University Chicago Stritch School of Medicine: Loyola
Loyola University Chicago Stritch School of Medicine: Loyola
Searches related to ki pharmacologie PDF
L'étude de l’effet pharmacologique (que l'on vient de définir) en traçant des courbes concentration-effet et en réalisant des études fonctionnelles L'étude de la sélectivité de la molécule Pharmacodynamie clinique Elle correspond à l'étude de l’effet thérapeutique
What is the Ki of a drug?
If a Ki is much larger than the maximal plasma drug concentrations a patient is typically exposed to from typical dosing, then that drug is not likely to inhibit the activity of that enzyme. The Ki can be used in the determining the [I]/Ki ratio as a tool for predicting drug-drug interactions.
What is Ki in biology?
Biology and chemistry 1 Ti (plant), also called K? 2 Ki, an equilibrium constant for a chemical reaction or process "i": dissociation constant applicable to process, abbreviated as "i". ... 3 Potassium iodide, chemical formula KI 4 Gene knockin or Knock-in, a genetic engineering method 5 Ki Database, a database of biochemical information
What is inhibitory constant (Ki) and IC50?
The Inhibitory Constant (Ki) and its Use in Understanding Drug Interactions Summary: The inhibitory constant (Ki) and the IC50 of a drug that is known to cause inhibition of a cytochrome P450 (CYP) enzyme have to do with the concentration needed to reduce the activity of that enzyme by half.
Why study medicine at KI?
Stockholm’s Karolinska Institutet (KI) specializes in medical and health sciences and enjoys a reputation for innovation and research in the field. KI is consistently ranked among the world’s top 10 medical universities. The university offers master’s degrees with the following specializations: nutrition science.
CENTER FOR DRUG EVALUATION AND
RESEARCH
APPLICATION NUMBER:
212028Orig1s000
MULTI-DISCIPLINE REVIEW
Summary Review
Office Director
Cross Discipline Team Leader Review
Clinical Review
Non-Clinical Review
Statistical Review
Clinical Pharmacology Review
NDA 212028 Multi-disciplinary Review and EvaluationDAYVIGO (lemborexant)
NDA/BLA Multi-Disciplinary Review and Evaluation�Application Type NDA
Application Number(s) 212028
Priority or Standard Standard
Submit Date(s) 12/27/2018
Received Date(s) 12/27/2018
PDUFA Goal Date 12/27/2019
Division/Office DP/ODE-I
Review Completion Date 12/20/2019
Established/Proper Name Lemborexant
(Proposed) Trade Name DAYVIGOPharmacologic Class Orexin receptor antagonist
Chemical Name (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3 fluorophenyl)-N-(5-fluoropyridin-2-yl) cyclopropanecarboxamideApplicant Eisai Inc.
Dosage Form Tablet
Applicant proposed Dosing
Regimen
5 to 10 mg by mouth nightly before bedtime
Applicant Proposed
Indication(s)/Population(s)
Treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance,Population: Adults
Applicant Proposed
SNOMED CT Indication
Disease Term for each
Proposed Indication
193462001 | Insomnia (disorder) |
Recommendation on
Regulatory Action
Approval
Recommended
Indication(s)/Population(s)
(if applicable) Treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenanceRecommended SNOMED
CT Indication Disease
Term for
Each Indication
(if applicable)193462001 | Insomnia (disorder) |
Recommended Dosing
Regimen
5 to 10 mg by mouth nightly before bedtime (b) (4)
1Version date: October 12, 2018
Reference ID: 4538004�
NDA 212028 Multi-disciplinary Review and EvaluationDAYVIGO (lemborexant)
Table of Contents�
Table of Tables ........................................................................ ........................................................ 5� Table of Figures........................................................................ ..................................................... 10�Reviewers of Multi-Disciplinary Review and Evaluation .............................................................. 14�
................................................................. 18� 1. � Executive Summary ........................................................................ ....................................... 20� Product Introduction........................................................................ .............................. 20�Conclusions on the Substantial Evidence of Effectiveness ............................................ 20�
Benefit-Risk Assessment ........................................................................ ........................ 22� Patient Experience Data........................................................................ ......................... 31� 2. � Therapeutic Context ........................................................................ ...................................... 32� Analysis of Condition........................................................................ .............................. 32�Analysis of Current Treatment Options ........................................................................
. 34�3. Regulatory Background ........................................................................
................................. 41�U.S. Regulatory Actions and Marketing History............................................................. 41�
Summary of Presubmission/Submission Regulatory Activity ........................................ 41�
Foreign Regulatory Actions and Marketing History....................................................... 42�
4. � Significant Issues From Other Review Disciplines Pertinent to Clinical Conclusions on� Efficacy and Safety........................................................................ ......................................... 43�Office of Scientific Investigations (OSI) ........................................................................
.. 43� Product Quality ........................................................................ ...................................... 44� Clinical Microbiology ........................................................................ .............................. 44�Devices and Companion Diagnostic Issues .................................................................... 44�
5.� Nonclinical Pharmacology/Toxicology........................................................................
........... 45� Executive Summary........................................................................ ................................ 45� Referenced NDAs, BLAs, DMFs........................................................................ ............... 48� ......................................... 49� ................................................ 55� ............................................... 61� General Toxicology........................................................................ .......................... 61� Genetic Toxicology........................................................................ .......................... 70� 2Version date: October 12, 2018
Reference ID: 4538004
NDA 212028 Multi-disciplinary Review and EvaluationDAYVIGO (lemborexant)
................................ 71�Reproductive and Developmental Toxicology........................................................ 72�
Other Toxicology Studies ........................................................................ ................ 84�6. Clinical Pharmacology........................................................................
.................................... 85� Executive Summary........................................................................ ................................ 85�Summary of Clinical Pharmacology Assessment............................................................ 87�
Pharmacology and Clinical Pharmacokinetics ........................................................ 87�
Comprehensive Clinical Pharmacology Review ............................................................. 91�
General Pharmacology and Pharmacokinetic Characteristics................................ 91�Clinical Pharmacology Questions........................................................................
.... 92� 7.� Sources of Clinical Data and Review Strategy ..................................................................... 118�
Table of Clinical Studies........................................................................ ........................ 118� Review Strategy........................................................................ .................................... 125�8. Statistical and Clinical and Evaluation ........................................................................
......... 126�Review of Relevant Individual Trials Used to Support Efficacy.................................... 126�
E2006-G000-303 ........................................................................ ........................... 126� E2006-G000-304 ........................................................................ ........................... 159�Integrated Review of Effectiveness ...................................................................... 191�
Review of Safety........................................................................ ................................... 198� Safety Review Approach ........................................................................ ............... 198�Review of the Safety Database ........................................................................
..... 198�Adequacy of Applicant's Clinical Safety Assessments .......................................... 210�
Safety Results........................................................................ ................................ 214�Analysis of Submission-Specific Safety Issues....................................................... 231�
Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability...... 251�Safety Analyses by Demographic Subgroups........................................................ 251�
Specific Safety Studies/Clinical Trials.................................................................... 254�
Additional Safety Explorations........................................................................
...... 256�Safety in the Postmarket Setting................................................................... 256�
Integrated Assessment of Safety................................................................... 257�
Statistical Issues ........................................................................ ................................... 258� 3Version date: October 12, 2018
Reference ID: 4538004
NDA 212028 Multi-disciplinary Review and EvaluationDAYVIGO (lemborexant)
Conclusions and Recommendations ........................................................................
.... 258�9. Advisory Committee Meeting and Other External Consultations....................................... 260�
10. Pediatrics ........................................................................
..................................................... 261�11. Labeling Recommendations ........................................................................
........................ 261� Prescription Drug Labeling ........................................................................ ............... 261�12. Risk Evaluation and Mitigation Strategies (REMS) .............................................................. 267�
13. Postmarketing Requirements and Commitment ................................................................ 268�
Postmarketing Requirements........................................................................ ........... 268� Maternal, Fetal, and Infant Outcomes of Women Exposed to Lemborexant268�Clinical PMR to Assess Respiratory Safety..................................................... 269�
Clinical Pharmacology PMCs........................................................................ .. 269�14. Appendices ........................................................................
.................................................. 271� References ........................................................................ ........................................ 271� Financial Disclosure ........................................................................ .......................... 274�Nonclinical Pharmacology/Toxicology...................................................................... 277�
OCP Appendices (Technical Documents Supporting OCP Recommendations)........ 277�Population Pharmacokinetic Analysis ........................................................... 277�
Physiologically based Pharmacokinetic (PBPK) Analyses .............................. 285� Driving Study Review........................................................................ ............. 297� Summary of Bioanalytical Method Validation and Performance.................. 309� 4Version date: October 12, 2018
Reference ID: 4538004
NDA 212028 Multi-disciplinary Review and EvaluationDAYVIGO (lemborexant)
Table of Tables
Table 1: DSM-5 Diagnostic Criteria for Insomnia Disorder........................................................... 32�
Table 2: Summary of Treatment Armamentarium Relevant to Insomnia Disorders ................... 34�
Table 3: In Vitro Properties of Lemborexant at Human OX1R and OX2R Compared to Suvorexant� ............................................... 50� Table 4: Lemborexant Pharmacokinetic Parameters After Single Intravenous and Oral� Administration to Male Rats ........................................................................ ......................... 55� Table 5: Lemborexant Pharmacokinetic Parameters After Single Intravenous and Oral�Administration to Male Monkeys........................................................................
.................. 55�Table 6: In Vitro Plasma Protein Binding of Lemborexant and Its Metabolites ........................... 56�
Table 7: Excretion of Radioactivity After a Single Oral Administration of [ 14C]Lemborexant to
Male Rats and Monkeys ........................................................................ ................................ 58�Table 8: Radioactivity In Plasma and Milk of Pregnant Lactating Rats......................................... 58�
Table 9: TK of Lemborexant in Rats on Day 183 ........................................................................
... 59�Table 10
: TK of Lemborexant in Monkeys on Day 269 ................................................................. 59�
Table 11: TK of Lemborexant In Pregnant Rats ........................................................................
.... 60�Table 12: TK of Lemborexant in Pregnant Rabbits .......................................................................
60�
Table 13: TK of Lemborexant in Pregnant Rats ........................................................................
.... 60�Table 14: TK of Lemborexant in Rats on Day 178 of Carcinogenicity Study................................. 60�
Table 15: Observations and Results: Changes From Control........................................................ 62�
Table 16: Observations and Results: Changes From Control........................................................ 64�
Table 17: Observations and Results........................................................................
...................... 73�Table 18: Observations and Results........................................................................
...................... 75�Table 19: Observations and Results........................................................................
...................... 76� Table 20: Incidence of Abnormal Lung Lobation in Rabbit Fetuses Compared With Historical� Controls ........................................................................ ......................................................... 77�Table 21: Observations and Results........................................................................
...................... 79�Table 22
: Observations and Results........................................................................ ...................... 83�Table 23: Acceptability of Specific Drug Information to Support Approval of Lemborexant....... 86�
Table 24: General Pharmacology and Pharmacokinetic Characteristics...................................... 91�
5Version date: October 12, 2018
Reference ID: 4538004
NDA 212028 Multi-disciplinary Review and EvaluationDAYVIGO (lemborexant)
Table 25: Itraconazole (ITZ) and Hydroxy-Itraconazole (OH-ITZ) PK Parameters Following a Single Oral Dose of Itraconazole Capsules or Solution Administered Under Fasting or Fed .................................................... 101�Table 26: Listing of Clinical Trials Relevant to NDA 212028 ....................................................... 119�
Table 27: Definition of Sleep Parameters for Study E2006-G000-303 ....................................... 133�
Table 28: Applicant Schedule of Procedures/Assessments in Study E2006-G000-303.............. 134�
Table 29: Revisions and Amendments to the E2006-G000-303 Protocol .................................. 138�
Table 30: Applicant's Description of Analysis Sets Used in E2006-G000-303 ............................ 140�
Table 31: Subject Disposition and Reason for Discontinuation From Study 303 Period 1......... 142�
Table 32: Applicant Summary of Major Protocol Deviations Study 303, Full Analysis Set......... 143�
Table 33: Demographic Characteristics of the Full Analysis Set for E2006-G000-303 ............... 145�
Table 34: Other Baseline Characteristics (Height, Weight, BMI), Full Analysis Set for E2006 G000 -303 ........................................................................ ..................................................... 146�Table 35: Baseline Scores for Primary and Key Secondary Endpoints in E2006-G000-303 ....... 147�
Table 36: Study Medication Compliance During Study E2006-G000-303 Period 1, Safety Analysis� ................................................................ 148�Table 37: Primary Efficacy Results on sSOL (Minutes), Study E2006-G000-303 ........................ 149�
Table 38: Sensitivity Analysis: MMRM Without Imputation Analysis Results on sSOL (Minutes),� Study E2006-G000-303........................................................................ ................................ 151� Table 39: Sensitivity Analysis: Jump to Placebo Analysis Results on sSOL (Minutes), Study E2006 G000 -303 ........................................................................ ..................................................... 152�Table 40: Efficacy Results on Key Secondary Endpoint sSE (%), Study E2006-G000-303........... 154�
Table 41: Efficacy Results on Key Secondary Endpoint sWASO (Minutes), Study E2006-G000-303� ............................................. 155� Table 42: Exploratory Analysis: Persistence vs. Loss of Effect from Month 1 During Phase 1,� .......................................... 157�Table 43: Applicant's Definition of Sleep Parameters for Study E2006-G000-304 .................... 165�
Table 44: Applicant's Schedule of Procedures/Assessments in Study E2006-G000-304 ........... 166�
Table 45: Applicant Reported Revisions/Amendments to the Protocol for Study E2006-G000-304� ............................................. 170�Table 46: Subject Disposition and Reasons for Discontinuation from Study 304 ...................... 172�
Table 47
: Major Protocol Deviations for Study E2006-G000-304, Full Analysis Set................... 173�Table 48: Demographic Characteristics of the Primary Efficacy Analysis for Study 304............ 175�
6Version date: October 12, 2018
Reference ID: 4538004
NDA 212028 Multi-disciplinary Review and EvaluationDAYVIGO (lemborexant)
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