[PDF] Multi-Discipline Review 19-Jul-2019 OX2R lemborexant





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KD CI50 KI

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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

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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 Evaluation

DAYVIGO (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 DAYVIGO

Pharmacologic Class Orexin receptor antagonist

Chemical Name (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3 fluorophenyl)-N-(5-fluoropyridin-2-yl) cyclopropanecarboxamide

Applicant 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 maintenance

Recommended 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)

1

Version date: October 12, 2018

Reference ID: 4538004�

NDA 212028 Multi-disciplinary Review and Evaluation

DAYVIGO (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� 2

Version date: October 12, 2018

Reference ID: 4538004

NDA 212028 Multi-disciplinary Review and Evaluation

DAYVIGO (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� 3

Version date: October 12, 2018

Reference ID: 4538004

NDA 212028 Multi-disciplinary Review and Evaluation

DAYVIGO (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� 4

Version date: October 12, 2018

Reference ID: 4538004

NDA 212028 Multi-disciplinary Review and Evaluation

DAYVIGO (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 [ 14

C]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�

5

Version date: October 12, 2018

Reference ID: 4538004

NDA 212028 Multi-disciplinary Review and Evaluation

DAYVIGO (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�

6

Version date: October 12, 2018

Reference ID: 4538004

NDA 212028 Multi-disciplinary Review and Evaluation

DAYVIGO (lemborexant)

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