204790Orig1s000 - Food and Drug Administration trials, DTG related liver injury could not be ruled...

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Transcript of 204790Orig1s000 - Food and Drug Administration trials, DTG related liver injury could not be ruled...

  • CENTER FOR DRUG EVALUATION AND RESEARCH

    APPLICATION NUMBER:

    204790Orig1s000

    PHARMACOLOGY REVIEW(S)

  • 1

    MEMO FOOD AND DRUG ADMINISTRATION Division of Antiviral Products Center for Drug Evaluation and Research

    Date: May 10, 2013 Reviewer: Hanan Ghantous, PhD, DABT Supervisory Interdisciplinary Scientist

    NDA #/SS#/date: 204-790/0000/12/17/2012

    Sponsor: ViiV Healthcare Drug Product: Dolutegravir (TIVICAY)

    Indication: Treatment of HIV infection

    Recommended Action: Nonclinical data support approval Dolutegravir (DTG) is an HIV integrase inhibitor (INI) that acts by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid integration. The applicant is seeking marketing approval for DTG as a treatment for HIV infection in combination with other antiretroviral agents in adults and children aged 12 to 18 years and weighing ≥40 kg. The proposed dosage for DTG is 50 mg once daily (QD) in treatment naïve and treatment experienced INI- naïve, HIV-infected adults and INI- naïve children 12 to 18 years old, weighing ≥40 kg. In INI-resistant subjects the DTG dose is 50 mg twice daily (BID). The applicant has submitted a complete nonclinical package of studies in mice, rats, rabbits, and nonhuman primates. In nonclinical toxicology studies, gastrointestinal effects including inflammation and hemorrhage were the principle finding in short term, subchronic, and chronic repeat dose studies, across species. Dolutegravir was not genotoxic, carcinogenic, or teratogenic and did not cause impairment of fertility in nonclinical studies. Conclusion: I concur with the primary nonclinical reviewer, Dr. Mark Seaton that the nonclinical data support an approval action for Dolutegravir as a treatment for HIV infection in combination with other antiretroviral agents in adults and children aged 12 to 18 years and weighing ≥40 kg.

    Reference ID: 3305805

  • --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ----------------------------------------------------

    HANAN N GHANTOUS 05/08/2013

    Reference ID: 3305805

  • Draft comments on N204-790 Dolutegravir

    From: A. Jacobs

    Date: 5/9/13

    1. I concur that there are no nonclinical approval issues and that the pregnancy category is appropriate.

    2. I made some editorial suggestions and comments on the text and on the description of the carcinogenicity studies, and the reviewer will address them as appropriate.

    Reference ID: 3305887

  • --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ----------------------------------------------------

    ABIGAIL C JACOBS 05/09/2013

    Reference ID: 3305887

  • DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE

    FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH

    PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION

    Application number: 204-790

    Supporting document/s: 0000

    Applicant’s letter date: 12/16/2012

    CDER stamp date: 12/17/2012

    Product: Dolutegravir (TIVICAY)

    Indication: Treatment of HIV infection in adults and children

    (aged 12 to 18 years and weighing 40 kilograms or

    more) in combination with other antiretroviral agents

    Applicant: ViiV Healthcare

    Review Division: Division of Antiviral Products

    Reviewer: Mark Seaton, Ph.D., DABT

    Supervisor/Team Leader: Hanan Ghantous, Ph.D., DABT

    Division Director: Debra Birnkrant, M.D.

    Project Manager: Sohail Mosaddegh, Pharm.D.

    Disclaimer Except as specifically identified, all data and information discussed below and necessary for approval of 204-790 are owned by ViiV Healthcare or are data for which ViiV Healthcare has obtained a written right of reference. Any information or data necessary for approval of 204-790 that ViiV Healthcare does not own or have a written right to reference constitutes one of the following: (1) published literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug, as reflected in the drug’s approved labeling. Any data or information described or referenced below from reviews or publicly available summaries of a previously approved application is for descriptive purposes only and is not relied upon for approval of 204-790.

    Reference ID: 3304189

  • NDA # 204-790 Reviewer Seaton

    2

    TABLE OF CONTENTS

    1.1 INTRODUCTION............................................................................................................. 6

    1.2 BRIEF DISCUSSION OF NONCLINICAL FINDINGS.............................................. 6

    1.3 RECOMMENDATIONS.................................................................................................. 7

    2 DRUG INFORMATION.................................................................................................... 8

    2.1 DRUG................................................................................................................................. 8

    2.2 RELEVANT INDS, NDAS, BLAS AND DMFS ............................................................ 9

    2.3 DRUG FORMULATION................................................................................................. 9

    2.4 COMMENTS ON NOVEL EXCIPIENTS..................................................................... 9

    2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ........................... 9

    2.6 PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ..................... 10

    2.7 REGULATORY BACKGROUND................................................................................ 10

    3 STUDIES SUBMITTED .................................................................................................. 10

    3.1 STUDIES REVIEWED .................................................................................................. 10

    3.2 STUDIES NOT REVIEWED......................................................................................... 15

    3.3 PREVIOUS REVIEWS REFERENCED ..................................................................... 16

    4 PHARMACOLOGY......................................................................................................... 16

    4.1 PRIMARY PHARMACOLOGY .................................................................................. 16

    4.2 SECONDARY PHARMACOLOGY ............................................................................ 16

    4.3 SAFETY PHARMACOLOGY...................................................................................... 16

    5 PHARMACOKINETICS/ADME/TOXICOKINETICS............................................... 16

    5.1 PK/ADME........................................................................................................................ 16

    6 GENERAL TOXICOLOGY............................................................................................ 20

    Reference ID: 3304189

  • NDA # 204-790 Reviewer Seaton

    3

    6.1 SINGLE-DOSE TOXICITY.......................................................................................... 20

    6.2 REPEAT-DOSE TOXICITY......................................................................................... 20

    7 GENETIC TOXICOLOGY ............................................................................................. 43

    8 CARCINOGENICITY ..................................................................................................... 44

    9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY................................ 52

    PRENATAL AND POSTNATAL DEVELOPMENTERROR! BOOKMARK NOT DEFINED.

    10 SPECIAL TOXICOLOGY STUDIES ............................................................................ 62

    11 INTEGRATED SUMMARY AND SAFETY EVALUATION..................................... 70

    12 APPENDIX/ATTACHMENTS ....................................................................................... 77

    Reference ID: 3304189

  • NDA # 204-790 Reviewer Seaton

    4

    Table of Tables

    Table 1: Result of Genotoxic Impurity Purging Study......................................................................9

    Table 2: Proposed Clinical Population and Dosing Regimen........................................................10

    Table 3: Toxicokinetics from 6-month Oral Toxicity Study of S-349572 sodium in Rats ............26

    Table 4: Plasma concentrations and toxicokinetic parameters in Male Monkeys on Day 14 of dosing (excerpted from sponsor) .....................................................................................31

    Table 5: Plasma concentrations and toxicokin