darunavir/cobicistat module 2.6.6 ... drv/cobi: 2.6.6 toxicology written summary 7 table 23:...

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    DARUNAVIR/COBICISTAT

    MODULE 2.6.6

    TOXICOLOGY WRITTEN SUMMARY

  • DRV/COBI: 2.6.6 Toxicology Written Summary

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    TABLE OF CONTENTS

    IN-TEXT FIGURES.................................................................................................................... 5

    IN-TEXT TABLES ..................................................................................................................... 6

    ABBREVIATIONS..................................................................................................................... 8

    1. BRIEF SUMMARY ..................................................................................................... 10

    2. SINGLE-DOSE TOXICITY ......................................................................................... 20 2.1. Darunavir .................................................................................................................... 20 2.2. Cobicistat .................................................................................................................... 21

    3. REPEAT-DOSE TOXICITY........................................................................................ 22 3.1. Darunavir .................................................................................................................... 22

    3.1.1. Rat.............................................................................................................. 22 3.1.1.1. Darunavir Alone ...................................................................................... 22 3.1.1.2. Darunavir Co-Administered with Ritonavir.............................................. 25 3.1.2. Dog............................................................................................................. 30 3.1.2.1. Darunavir Alone ...................................................................................... 30 3.1.2.2. Darunavir Co-Administered with Ritonavir.............................................. 32

    3.2. Cobicistat .................................................................................................................... 32 3.2.1. Rats ............................................................................................................ 33 3.2.1.1. Cobicistat Alone ...................................................................................... 33 3.2.1.2. Cobicistat Co-Administered with Atazanavir........................................... 39 3.2.2. Dogs ........................................................................................................... 42

    4. GENOTOXICITY ........................................................................................................ 47 4.1. Darunavir .................................................................................................................... 47

    4.1.1. In Vitro Nonmammalian Cell System ......................................................... 47 4.1.2. In Vitro Mammalian Cell System................................................................ 47 4.1.3. In Vivo Mammalian System........................................................................ 48

    4.2. Cobicistat .................................................................................................................... 48 4.2.1. In Vitro Nonmammalian Cell System ......................................................... 48 4.2.2. In Vitro Mammalian Cell System................................................................ 49 4.2.3. In Vivo Mammalian System........................................................................ 50

    5. CARCINOGENICITY.................................................................................................. 51 5.1. Darunavir .................................................................................................................... 51

    5.1.1. Long Term Studies ..................................................................................... 51 5.1.1.1. Mouse Studies ........................................................................................ 51 5.1.1.2. Rat Studies ............................................................................................. 54 5.1.2. Short- or Medium-Term Studies................................................................. 57 5.1.3. Other Studies ............................................................................................. 57

    5.2. Cobicistat .................................................................................................................... 58 5.2.1. Long Term Studies ..................................................................................... 58 5.2.1.1. Mouse Studies ........................................................................................ 58 5.2.1.2. Rat Studies ............................................................................................. 64 5.2.2. Short- or Medium-Term Studies................................................................. 68 5.2.3. Other Studies ............................................................................................. 68

    6. REPRODUCTIVE AND DEVELOPMENTAL TOXICITY........................................... 68 6.1. Darunavir .................................................................................................................... 68

    6.1.1. Fertility and Early Embryonic Development ............................................... 69 6.1.2. Embryo-Fetal Development ....................................................................... 70

  • DRV/COBI: 2.6.6 Toxicology Written Summary

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    6.1.2.1. Rats......................................................................................................... 70 6.1.2.1.1.Darunavir Alone........................................................................................... 70 6.1.2.1.2.Darunavir Co-Administered with Ritonavir .................................................. 71 6.1.2.2. Rabbits .................................................................................................... 74 6.1.2.2.1.Darunavir Alone........................................................................................... 74 6.1.2.2.2.Darunavir Co-Administered with Ritonavir .................................................. 76 6.1.2.3. Mice......................................................................................................... 76 6.1.2.3.1.Darunavir Alone........................................................................................... 76 6.1.2.3.2.Darunavir Co-Administered with Ritonavir .................................................. 76 6.1.2.4. Minipigs ................................................................................................... 78 6.1.3. Prenatal and Postnatal Development, Including Maternal Function .......... 80 6.1.3.1. Darunavir Alone ...................................................................................... 80 6.1.3.2. Darunavir Co-Administered with Ritonavir.............................................. 82 6.1.4. Studies in which the Offspring are Dosed.................................................. 85 6.1.4.1. Darunavir Alone ...................................................................................... 85 6.1.4.2. Darunavir Co-Administered with Ritonavir.............................................. 85

    6.2. Cobicistat .................................................................................................................... 86 6.2.1. Fertility and Early Embryonic Development ............................................... 86 6.2.2. Embryo-Fetal Development ....................................................................... 88 6.2.2.1. Rats......................................................................................................... 88 6.2.2.2. Rabbits .................................................................................................... 90 6.2.3. Prenatal and Postnatal Development, Including Maternal Function .......... 92 6.2.4. Studies in which the Offspring are Dosed.................................................. 97

    7. LOCAL TOLERANCE................................................................................................ 97 7.1. Darunavir .................................................................................................................... 97

    7.1.1. Skin Sensitization: Local Lymph Node Assay............................................ 97 7.1.2. In Vivo Skin Irritation .................................................................................. 97 7.1.3. In Vitro Ocular Irritation .............................................................................. 98

    7.2. Cobicistat .................................................................................................................... 98 7.2.1. Skin Sensitization: Local Lymph Node Assay............................................ 98 7.2.2. In Vivo Skin Irritation .................................................................................. 99 7.2.3. In Vitro Ocular Irritation .............................................................................. 99 7.2.4. Phototoxicity ............................................................................................... 99

    8. OTHER TOXICITY STUDIES..................................................................................... 99 8.1. Darunavir .................................................................................................................... 99

    8.1.1. Immunotoxicity ........................................................................................... 99 8.1.2. Mechanistic Studies ...