FACTORS AFFECTING PULMONARY TARGETING OF INHALED CORTICOSTEROIDS By KAI WU A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2006 Copyright 2006 by Kai Wu For my Waipo, Baba, Mama, Gege and Laopo. ACKNOWLEDGMENTS I extend my appreciation and grateful thanks to Dr. Guenther Hochhaus for guiding me through the four years of Ph.D. study, giving me excellent suggestions and always supporting me. I would like to thank the members of my supervisory committee, Dr. Hartmut Derendorf, Dr. Jeffrey Hughes, and Dr. Saeed R. Khan, for their valuable and kind advice throughout my research. I take this opportunity to express my gratitude to Yufei Tang for her invaluable technical assistance. I would like to thank all the secretaries, Jame Ketcham, Andrea Tucker and Patricia Khan， for their technical and administrative assistance. I thank my group members, Yaning, Manish, Intira, Vikram, Sriks, Zia, Elanor, Keerti, Navin, Nasha and other graduate students and post-docs in the department for their assistance and friendship. Especially I want to thank all my friends, Weihui, Chao, Jeff, Victor, Aixin, Kai and Zhen, Chengguan and Qin, Yipeng and Hongxiao and all my other friends for their help and support that have made my stay in Gainesville a pleasant experience. I want to express my deep gratitude and love for my parents, brother and other family members for their unconditional support and encouragement of my academic pursuits over the years. Last, but not least, I want to thank my lovely wife, Ling, for her 120% support, full understanding and timely encouragement. Without her, I would not have been able to achieve any of what I have achieved. iv TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................................................................................. iv LIST OF TABLES........................................................................................................... viii LIST OF FIGURES ........................................................................................................... ix ABSTRACT....................................................................................................................... xi CHAPTER 1 INTRODUCTION ........................................................................................................1 Asthma..........................................................................................................................3 Mechanism of Action of Corticosteroids in Asthma ....................................................6 Disposition of Inhaled Corticosteroids .........................................................................8 Inhalation Device..........................................................................................................9 Physical Characteristics of Patient..............................................................................13 Pharmacokinetic and Pharmacodynamic Properties of ICS .......................................14 Pharmacokinetic Properties.................................................................................14 Prodrug.........................................................................................................14 Mucociliary Clearance .................................................................................15 Pulmonary Residence Time .........................................................................15 Bioavailability ..............................................................................................16 Clearance......................................................................................................17 Drug Distribution .........................................................................................18 Half-life ........................................................................................................19 Protein Binding ............................................................................................19 Objectives of the Study...............................................................................................21 2 IN-VITRO COMPARISION OF FLUTICASONE RESPIRABLE DOSE FROM A METERED DOSE INHALER AND THREE RIGID VALVED HOLDING CHAMBERS ..............................................................................................................22 Introduction.................................................................................................................22 Materials and Methods ...............................................................................................23 Chemicals and Devices........................................................................................23 Sample Collection ...............................................................................................23 Fluticasone Propionate Assay..............................................................................26 v Data Analysis.......................................................................................................26 Results.........................................................................................................................27 Discussion and Conclusion.........................................................................................29 3 PLASMA CONCENTRATIONS AND PHARMACOKINETICS PROFILES OF INHALED CORTICOSTEROIDS AND THEIR RELATION TO LUNG FUNCTION IN ASTHMA.........................................................................................32 Introduction.................................................................................................................32 Methods ......................................................................................................................33 Subjects................................................................................................................33 Measurements......................................................................................................33 Lung function ...............................................................................................33 Plasma drug assays.......................................................................................33 Protocol................................................................................................................34 Analysis ...............................................................................................................35 Results .................................................................................................................35 Plasma drug concentrations and pharmacokinetic profiles ..........................37 Relation between lung function and AUC ...................................................38 Discussion...................................................................................................................40 Plasma Drug Concentrations and Pharmacokinetic Profiles ..............................41 Relation Between Lung Function and AUC .......................................................42 Conclusion ..................................................................................................................43 4 FLUTICASONE AND BUDESONIDE CONCENTRATIONS AFTER INHALATION EFFECT OF BRONCHOCONSTRICTION....................................45 Introduction.................................................................................................................45 Methods ......................................................................................................................46 Subjects................................................................................................................46 Measurements......................................................................................................46 Spirometry....................................................................................................46 Methacholine inhalation challenge...............................................................46 Drug assays ..................................................................................................47 Protocol................................................................................................................47 Analysis ...............................................................................................................48 Results.........................................................................................................................48 Discussion...................................................................................................................51 5 EVALUATION OF THE ADMINISTRATION TIME EFFECT ON THE CUMULATIVE CORTISOL SUPPRESSION AND CUMULATIVE LYMPHOCYTES SUPPRESSION FOR ONCE-DAILY INHALED CORTICOSTEROIDS................................................................................................55 Introduction.................................................................................................................55 Methods ......................................................................................................................57 Historic Data........................................................................................................57 vi Population Pharmacokinetic/Pharmacodynamic Analysis..................................58 Pharmacokinetic analysis .............................................................................58