1.  Executive Summary ................................................................................................................................

1

    1.1 Recommendations and Comments to Sponsor .......................................................................................

2

2  Table of Contents ....................................................................................................................................

4

3  Summary of Clinical Pharmacology and Biopharmaceutics Findings .............................................................

5

    3.1  Background .......................................................................................................................................

5

    3.2  Current Submission ............................................................................................................................

5

4  Question-Based Review ...........................................................................................................................

8

    4.1  General Attributes .............................................................................................................................

8

    4.2  General Clinical Pharmacology ...........................................................................................................

10

    4.3  Intrinsic Factors .................................................................................................................................

13

    4.4  Extrinsic Factors ................................................................................................................................

15

    4.5  General Biopharmaceutics ..................................................................................................................

17

    4.6  Bioanalytical Method .........................................................................................................................

28

5  Detailed labeling recommendations (only the changed sections are included here) .........................................

30

6  Appendices ..............................................................................................................................................

33

    6.1  Sponsor Proposed Package Insert (Annotated) With OCPB Comments Highlighted ...............................

33

    6.2  Clinical Pharmacology and Biopharmaceutics Individual Study Reviews ................................................

62

          6.2.1     PET STUDY OF DOPAMINE TRANSPORTER OCCUPANCY ..........................................

62

          6.2.2     FOOD-EFFECT STUDY .......................................................................................................

67

          6.2.3     DOSAGE STRENGTH EQUIVALENCE ..............................................................................

74

          6.2.4     BIOEQUIVALENCE STUDY ..............................................................................................

80

          6.2.5     BIOANALYTICAL METHOD .............................................................................................

88

          6.2.6     DISSOLUTION METHOD DEVELOPMENT ......................................................................

91

    6.3  Consult Reviews (Including Pharmacometric Reviews) ........................................................................

96

    6.4  Cover Sheet and OCPB Filing/Review Form ........................................................................................

97