Phoenix WinNonlin®
`User’s Guide
`Applies to:
`Phoenix WinNonlin 8.1
`
`AMN1085
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`

`

`Phoenix WinNonlin Version 8.1
`Phoenix® WinNonlin®, Phoenix NLME™, IVIVC Toolkit™, CDISC® Navigator, AutoPilot Toolkit™, Job Management System™
`(JMS™), Pharsight Knowledgebase Server™ (PKS™), Trial Simulator™, Validation Suite™ copyright ©2005-2018, Certara, L.P. All
`rights reserved. This software and the accompanying documentation are owned by Certara, L.P. The software and the accompanying docu-
`mentation may be used only as authorized in the license agreement controlling such use. No part of this software or the accompanying doc-
`umentation may be reproduced, transmitted, or translated, in any form or by any means, electronic, mechanical, manual, optical, or
`otherwise, except as expressly provided by the license agreement or with the prior written permission of Certara, L.P.
`This product may contain the following software that is provided to Certara, L.P. under license: Formula One® copyright 1993-2018 Open-
`Text Corporation. All rights reserved. Microsoft® .NET Framework copyright 2018 Microsoft Corporation. All rights reserved. Tab Pro
`ActiveX 2.0.0.45 copyright 1996-2018, GrapeCity, Inc. All rights reserved. Sentinel™ RMS 8.4.0.900 copyright 2006-2018 Gemalto NV.
`All rights reserved. Microsoft XML Parser version 3.0 copyright 1998-2018 Microsoft Corporation. All rights reserved. Websites Screen-
`shot DLL 1.6 copyright 2008-2018 WebsitesScreenshot.com. All rights reserved. Certara, L.P. has agreement to use and redistribute licenses
`for the following software: Syncfusion Essential Studio Enterprise 15.4.0.17 copyright 2001-2018 Syncfusion Inc. All rights reserved. Min-
`imal Gnu for Windows (MinGW, http://mingw.org/), copyright 2004-2018 Free Software Foundation, Inc. This product may also contain the
`following royalty free software: DotNetbar 1.0.0.24030 (with custom code changes) copyright 1996-2018 DevComponents LLC. All rights
`reserved. Xceed zip Library 2.0.116.0 copyright 1994-2018 Xceed Software Inc. All rights reserved. IMSL® copyright 2018 Rogue Wave
`Software, Inc. All rights reserved.
`Information in the documentation is subject to change without notice and does not represent a commitment on the part of Certara, L.P. The
`documentation contains information proprietary to Certara, L.P. and is for use by its affiliates' and designates' customers only. Use of the
`information contained in the documentation for any purpose other than that for which it is intended is not authorized. NONE OF CERTARA,
`L.P., NOR ANY OF THE CONTRIBUTORS TO THIS DOCUMENT MAKES ANY REPRESENTATION OR WARRANTY, NOR SHALL ANY WARRANTY BE
`IMPLIED, AS TO THE COMPLETENESS, ACCURACY, OR USEFULNESS OF THE INFORMATION CONTAINED IN THIS DOCUMENT, NOR DO THEY
`ASSUME ANY RESPONSIBILITY FOR LIABILITY OR DAMAGE OF ANY KIND WHICH MAY RESULT FROM THE USE OF SUCH INFORMATION.
`Destination Control Statement
`All technical data contained in the documentation are subject to the export control laws of the United States of America. Disclosure to
`nationals of other countries may violate such laws. It is the reader's responsibility to determine the applicable regulations and to comply with
`them.
`United States Government Rights
`This software and accompanying documentation constitute “commercial computer software” and “commercial computer software docu-
`mentation” as such terms are used in 48 CFR 12.212 (Sept. 1995). United States Government end users acquire the Software under the fol-
`lowing terms: (i) for acquisition by or on behalf of civilian agencies, consistent with the policy set forth in 48 CFR 12.212 (Sept. 1995); or
`(ii) for acquisition by or on behalf of units of the Department of Defense, consistent with the policies set forth in 48 CFR 227.7202-1 (June
`1995) and 227.7202-3 (June 1995). The manufacturer is Certara, L.P., 100 Overlook Center, Suite 101, Princeton, New Jersey, 08540.
`Trademarks
`AutoPilot Toolkit, IVIVC Toolkit, Job Management System, JMS, NLME, Pharsight Knowledgebase Server, PKS, Phoenix, Trial Simula-
`tor, Validation Suite, WinNonlin are trademarks or registered trademarks of Certara, L.P. NONMEM is a registered trademark of ICON
`Development Solutions. S-PLUS is a registered trademark of Insightful Corporation. SAS and all other SAS Institute Inc. product or service
`names are registered trademarks or trademarks of SAS Institute Inc. in the USA and other countries. Sentinel RMS is a trademark of
`Gemalto NV. Microsoft, MS, .NET, SQL Server Compact Edition, the Internet Explorer logo, the Office logo, Microsoft Word, Microsoft
`Excel, Microsoft PowerPoint®, Windows, the Windows logo, the Windows Start logo, and the XL design (the Microsoft Excel logo) are
`trademarks or registered trademarks of Microsoft Corporation. Pentium 4 and Core 2 are trademarks or registered trademarks of Intel Cor-
`poration. Adobe, Acrobat, Acrobat Reader, and the Adobe PDF logo are registered trademarks of Adobe Systems Incorporated. All other
`brand or product names mentioned in this documentation are trademarks or registered trademarks of their respective companies or organiza-
`tions.
`Additional third party software acknowledgements
`Software for Locally-Weighted Regression
`The authors of this software are Cleveland, Grosse, and Shyu. Copyright © 1989, 1992 by AT&T. Permission to use, copy, modify, and dis-
`tribute this software for any purpose without fee is hereby granted, provided that this entire notice is included in all copies of any software
`which is or includes a copy or modification of this software and in all copies of the supporting documentation for such software.
`This software is being provided “as is”, without any express or implied warranty. In particular, neither the authors nor AT&T make any rep-
`resentation or warranty or any kind concerning the merchantability of this software or its fitness for any particular purpose.
`LAPACK
`Copyright © 1992-2007 The University of Tennessee. All rights reserved.
`Redistribution and use in source and binary forms, with or without modification, are permitted provided that the following conditions are
`met:
`Redistributions of source code must retain the above copyright notice, this list of conditions and the following disclaimer.
`Redistributions in binary form must reproduce the above copyright notice, this list of conditions and the following disclaimer listed in this
`license in the documentation and/or other materials provided with the distribution.
`Neither the name of the copyright holders nor the names of its contributors may be used to endorse or promote products derived from this
`software without specific prior written permission.
`
`AMN1085
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`

`

`This software is provided by the copyright holders and contributors “as is” and any express or implied warranties, including, but not limited
`to, the implied warranties of merchantability and fitness for a particular purpose are disclaimed. In no event shall the copyright owner or
`contributors be liable for any direct, indirect, incidental, special, exemplary, or consequential damages (including, but not limited to, pro-
`curement of substitute goods or services; loss of use, data, or profits; or business interruption) however caused and on any theory of liability,
`whether in contract, strict liability, or tort (including negligence or otherwise) arising in any way out of the use of this software, even if
`advised of the possibility of such damage.
`NLog
`Copyright © 2004-2006 Jaroslaw Kowalski <jaak@jkowalski.net>. All rights reserved.
`Redistribution and use in source and binary forms, with or without modification, are permitted provided that the following conditions are
`met:
`Redistributions of source code must retain the above copyright notice, this list of conditions and the following disclaimer.
`Redistributions in binary form must reproduce the above copyright notice, this list of conditions and the following disclaimer in the docu-
`mentation and/or other materials provided with the distribution.
`Neither the name of Jaroslaw Kowalski nor the names of its contributors may be used to endorse or promote products derived from this soft-
`ware without specific prior written permission.
`This software is provided by the copyright holders and contributors “as is” and any express or implied warranties, including, but not limited
`to, the implied warranties of merchantability and fitness for a particular purpose are disclaimed. In no event shall the copyright owner or
`contributors be liable for any direct, indirect, incidental, special, exemplary, or consequential damages (including, but not limited to, pro-
`curement of substitute goods or services; loss of use, data, or profits; or business interruption) however caused and on any theory of liability,
`whether in contract, strict liability, or tort (including negligence or otherwise) arising in any way out of the use of this software, even if
`advised of the possibility of such damage.
`
`AMN1085
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`

`

`Certara, L.P.
`100 Overlook Center, Suite 101, Princeton, NJ, 08540 USA
`Telephone: +1.609.716.7900
`www.certara.com
`
`AMN1085
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`

`

`Contents
`
`List of Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .xv
`
`List of Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxi
`
`Chapter 1
`
`Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25
`The Phoenix platform . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
`Certara contact information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
`
`Chapter 2
`
`Noncompartmental Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27
`Object user interface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
`Main Mappings panel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
`Dosing panel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
`Slopes Selector panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
`Slopes panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
`Partial Areas panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
`Therapeutic Response panel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
`Units panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
`Parameter Names panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
`Options tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
`User Defined Parameters tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
`Rules tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
`Plots tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
`Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
`Worksheet output . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
`Plot output . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
`NCA computations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
`Time deviations in steady-state data. . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
`Data checking and pre-treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
`Lambda Z or slope estimation settings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
`Lambda Z or slope range selection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
`Calculation of Lambda Z . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
`Calculation of slopes for effect data. . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
`Limitations of Lambda Z and slope estimation . . . . . . . . . . . . . . . . . . . 47
`Partial areas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
`Therapeutic response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
`Therapeutic response windows. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
`
`v
`
`AMN1085
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`

`

`Phoenix WinNonlin
`User’s Guide
`
`AUC calculation and interpolation formulas. . . . . . . . . . . . . . . . . . . . . . . . . 51
`Sparse sampling computations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
`Drug effect computations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
`NCA output parameters and their computation formulas . . . . . . . . . . . . . . . 55
`Plasma or serum data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
`Urine data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
`Sparse sampling (pre-clinical) data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
`Drug effect data - model 220 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
`User defined parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
`References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
`
`Bioequivalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .69
`Object user interface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
`Main Mappings panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
`Model tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
`Fixed Effects tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
`Variance Structure tab. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
`Options tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
`General Options tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
`Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
`Average bioequivalence output. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
`Population/Individual bioequivalence output . . . . . . . . . . . . . . . . . . . . . 78
`Text output . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
`Ratios test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
`Introduction to bioequivalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
`Bioequivalence studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
`The model and the data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
`Linear model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
`Covariance structure types in the Bioequivalence object . . . . . . . . . . . . 81
`Missing data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
`Variable name and data limits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
`Average bioequivalence study designs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
`Recommended models for average bioequivalence . . . . . . . . . . . . . . . . 84
`Least squares means . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
`Classical intervals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
`Two one-sided t-tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
`Power of the two one-sided t-tests procedure . . . . . . . . . . . . . . . . . . . . . 89
`Anderson-Hauck test. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
`Power for 80/20 Rule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
`Tests for equal variances. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
`Population and individual bioequivalence. . . . . . . . . . . . . . . . . . . . . . . . . . . 93
`Bioequivalence criterion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
`Computational details . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
`References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
`
`Crossover . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .101
`Object user interface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
`Main Mappings panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
`Options tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
`
`Chapter 3
`
`Chapter 4
`
`vi
`
`AMN1085
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`

`

`Table of Contents
`
`Chapter 5
`
`Chapter 6
`
`Chapter 7
`
`Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
`Crossover methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
`Data and assumptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
`Descriptive analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
`Hypothesis testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
`
`Convolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .107
`Object user interface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
`Input Mappings panel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
`UIR panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
`Options tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
`Plots tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
`Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
`Convolution units . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
`Convolution function types and data requirements. . . . . . . . . . . . . . . . . . . 112
`
`Deconvolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .115
`Object user interface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
`Main Mappings panel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
`Exp Terms panel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
`Dose panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
`Observed Times panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
`Options tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
`Plots tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
`Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
`Deconvolution methodology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
`Linearity assumptions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
`Deconvolution through convolution methodology. . . . . . . . . . . . . . . . 124
`
`Linear Mixed Effects Modeling . . . . . . . . . . . . . . . . . . . . . . . . . .127
`Object user interface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
`Main Mappings panel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
`Fixed Effects tab. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
`Variance Structure tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
`Contrasts tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
`Estimates tab. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
`Least Squares Means tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
`General Options tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
`Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
`Worksheet output . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
`Text output . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
`Output explanations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
`Computational details . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
`Restricted maximum likelihood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
`Newton algorithm for maximization of restricted likelihood. . . . . . . . 142
`Starting values . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
`Convergence criterion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
`Satterthwaite approximation for degrees of freedom . . . . . . . . . . . . . . 143
`
`vii
`
`AMN1085
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`

`

`Phoenix WinNonlin
`User’s Guide
`
`Data limits and constraints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
`Linear mixed effects example . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
`General linear mixed effects model. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
`Construction of the X matrix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
`Linear combinations of elements of beta . . . . . . . . . . . . . . . . . . . . . . . 151
`Determining estimability numerically . . . . . . . . . . . . . . . . . . . . . . . . . 152
`Substitution of estimable functions for non-estimable functions . . . . . 153
`Fixed effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
`Output parameterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
`Crossover example continued . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
`Variance structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
`Repeated effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
`Random effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
`Covariance structure types in the Linear Mixed Effects object . . . . . . 160
`Contrasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
`Joint versus single contrasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
`Nonestimability of contrasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
`Degrees of freedom. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
`Other options. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
`Estimates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
`Least squares means . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
`Comparing the Linear Mixed Effects object to SAS PROC MIXED . . . . . 165
`References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
`
`NonParametric Superposition . . . . . . . . . . . . . . . . . . . . . . . . . . .169
`Object user interface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
`Main Mappings panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
`Administered Dose panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
`Terminal Phase panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
`Dosing panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
`Options tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
`Plots tab. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
`Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
`Methodology and data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
`Computation method. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
`
`Semicompartmental Modeling . . . . . . . . . . . . . . . . . . . . . . . . . . .175
`Object user interface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
`Main Mappings panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
`Options tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
`Plots tab. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
`Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
`Semicompartmental modeling capabilities . . . . . . . . . . . . . . . . . . . . . . . . . 178
`Data and assumptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
`Computation method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
`References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
`
`Chapter 8
`
`Chapter 9
`
`Chapter 10 WNL Classic Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .181
`
`viii
`
`AMN1085
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`

`

`Table of Contents
`
`Object user interface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
`Main Mappings panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
`Dosing panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
`Initial Estimates panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
`PK Parameters panel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
`Units panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
`Stripping Dose panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
`Constants panel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
`Format panel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
`Model Selection tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
`Linked Model tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
`Weighting/Dosing Options tab. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
`Parameter Options tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
`Engine Settings tab. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
`Plots tab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
`Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
`Worksheet output . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
`Plot output . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
`Indirect Response models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
`Model 51 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
`Model 52 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
`Model 53 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
`Model 54 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
`Linear models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
`Michaelis-Menten models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
`Model 301 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
`Model 302 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
`Model 303 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
`Model 304 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
`Dosing constants for the Michaelis-Menten model . . . . . . . . . . . . . . . 201
`Pharmacodynamic models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
`Model 101 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
`Model 102 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
`Model 103 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
`Model 104 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
`Model 105 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
`Model 106 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
`Model 107 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
`Model 108 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
`Pharmacokinetic models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
`Model 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
`Model 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
`Model 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
`Model 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
`Model 5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
`Model 6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
`Model 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
`Model 8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
`Model 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
`
`ix
`
`AMN1085
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2