Evaluation of the Allometric Exponents in Prediction of Human Drug Clearance

Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2014 Evaluation of the Allometric Exponents in Prediction of Human Drug Clearance Da Zhang Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Other Pharmacy and Pharmaceutical Sciences Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/3533 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. ©Da Zhang, 2014 All Rights Reserve EVALUATION OF THE ALLOMETRIC EXPONENTS IN PREDICTION OF HUMAN DRUG CLEARANCE A Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University By Da Zhang Master of Science, University of Arizona, 2004 Director: F. Douglas Boudinot, Ph.D. Professor, School of Pharmacy, VCU Virginia Commonwealth University Richmond, Virginia August, 2014 ACKNOWLEDGEMENTS First and foremost, I would like to sincerely thank my advisor, Dr. F. Douglas Boudinot, for giving me the opportunity to pursue graduate studies under his guidance and for his continuous professional support, guidance, encouragement and patience throughout my graduate program. He was always delighted in sharing his vast knowledge and kind warmth. I would also like to thank Dr. Ahmad for his scientific advice and support through the complet ion of my degree. He has been a kind and helpful mentor for me. I would like to acknowledge my graduate committee members, Drs. Susanna Wu-Pong, Patricia W. Slattum, Phillip M. Gerk and Alaa Ahmad for their advice, time for serving on my committee as well as their timely guidance and input. My parents, Defen Zheng and Yuliang Zhang, my sister, Lei Zhang and other family members for their unconditional love and support. Last, but not least, my husband, Huadong, and sons, Albert and Daniel for their understanding and love during these years. The ir unwavering patience and encouragement was crucial for the successful completion of my part-time Ph.D. ii TABLE OF CONTENTS ACKNOWLEDGEMENTS ....................................................................................................ii TABLE OF CONTENTS....................................................................................................... iii LIST OF TABLES.................................................................................................................vi LIST OF FIGURES .............................................................................................................. vii LIST OF ABBREVIATIONS ................................................................................................ x ABSTRACT......................................................................................................................... xiii CHAPTERS 1. INTRODUCTION ............................................................................................................. 1 Reference list ................................................................................................................ 7 2. IMPLEMENTATION OF NON-LINEAR MIXED EFFECT MODELING APPROACH IN ALLOMETRIC SCALING FOR HUMAN CLEARANCE PREDICTION .................... 9 1_Abstract ................................................................................................................... 9 2_Introduction.............................................................................................................11 3_ Materials and Methods............................................................................................15 4_Results ....................................................................................................................24 iii 5_Discussion...............................................................................................................29 Reference List .............................................................................................................53 3. MODELING AND SIMULATION APPROACH FOR CHARACTERIZING AND EVALUATING THE SINGLE SPECIES ALLOMETIC SCALING ..................................90 1_Abstract ..................................................................................................................90 2_Introduction.............................................................................................................91 3_Methods ..................................................................................................................94 4_Results and Discussion ............................................................................................97 Reference List ........................................................................................................... 107 4. EVALUATION OF METHODS IN ANALYZING ALLOMETRIC POWER FUNCTIONS IN PREDICTING HUMAN PHARMACOKINETICS: A COMPARISON OF LOG-LOG TRANSFORMATION FOLLOWED BY LINEAR REGRESSIOIN VERSUS DIRECT NONLIEAR REGRESSION ............................................................... 118 1_Abstract ................................................................................................................ 118 2_Introduction........................................................................................................... 120 3_ Methods ............................................................................................................... 124 iv 4_Results and Discussion .......................................................................................... 128 Reference List ........................................................................................................... 142 5. CONCLUSIONS AND FUTURE DIRECTIONS ........................................................... 149 VITA .................................................................................................................................. 152 v LIST OF TABLES Table 2.1. Drug Clearance values in Different Species with Physicochemical and DMPK Properties ...............................................................................................................................32 Table 2.2. AS Parameter Estimation of Basic Structure Model and Final Model Based on the Nonlinear MEM Approach......................................................................................................45 Table 2.3. Physicochemical and DMPK properties of compounds in the database ....................46 Table 3.1. Summary Statistics of the Estimated AS Exponent Distribution for Single species AS Rat, Dog and Monkey Methods Based on the Literature Data................................................. 106 Table 3.2. Statistical Analysis of the Correlations of Exponents from Three Different Single species AS with the Physicochemical and DMPK Properties .................................................. 106 Table 4.1. Estimated AS Exponent Central Tendencies and Percent Difference between NLS with Weightings Compared to LL-LR Based on Data Set including humans ........................... 129 Table 4.2. Human CL Prediction Performance Comparison Among NLS and LL-LR: AAFE and AFE, Percentage of Fold-Errors out of Ranges [0.1, 10] and [0.3, 3] ................................ 133 Table 4.3. Comparison Among MLP and BrW corrected LL-LR and simple LL-LR: AAFE and AFE, Percentage of Fold-Errors out of Ranges [0.1, 10] and [0.3, 3] ...................................... 137 vi LIST OF FIGURES Figure 2.1. Distribution of the physicochemical and DMPK properties ....................................47 Figure 2.2. Goodness of Fit Plots of the Final AS nonlinear MEM model. (A) and (D). Population Model Predicted versus Observed CLs; (B) and (E). Individual predicted based on Final Model versus observed CLs; (C). Conditional Weighted Residuals versus Log transformed Body Weight; .........................................................................................................................49 Figure 2.3. Distribution and Central Tendency of Observed versus Model Predicted Human CL ..............................................................................................................................................50 Figure 2.4. Distribution of Model Estimated AS Exponent versus Literature Reports ...............52 Figure 3.1. Single species AS Exponent Central Tendency and Distributions based on literature collected data of CLrat-CLhuman (n = 249), CLdog-CLhuman (n = 231) and CLmonkey-CLhuman (n = 156) ............................................................................................................................................ 101 Figure 3.2. Distributions of Predicted Human CL (ml/min) values for 10,000 simulations Based on Rat Single species AS Approach. Linear Scale and Log-transformed Scale are Presented in Upper and Lower Plots, respectively. .................................................................................... 103 vii Figure 3.3. Distributions of Predicted Human CL (ml/min) for 10,000 simulations Based on Dog Single species AS Approach. Linear Scale and Log-transformed Scale are Presented in Upper and Lower Plots, respectively................................................................................................ 104 Figure 3.4. Distributions of Predicted Human CL (ml/min) for 10,000 simulations Based on

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