Pharmacokinetics and Pharmacodynamics of Corticosteroid Prodrugs and Soft Drugs
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PHARMACOKINETICS AND PHARMACODYNAMICS OF CORTICOSTEROID PRODRUGS AND SOFT DRUGS By JULIA WINKLER 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 2004 Copyright 2004 by Julia Winkler This work is dedicated to my parents, my husband, and my son. ACKNOWLEDGMENTS I would like to express my gratitude and appreciation to my supervisor, Dr. Hartmut Derendorf, for giving me the opportunity to work on my Ph.D. I also would like to thank him for his constant guidance, patience, and encouragement during those 4 years of course work presented in this dissertation. My special thanks go to the cochair of my supervisory committee, Dr. Nicolas Bodor, for his guidance throughout my doctoral research. I also thank the members of my supervisory committee (Dr. Günther Hochhaus and Dr. Peter Stacpoole) for their guidance, advice and availability. I would like to thank Dr. Veronika Butterweck and Dr. Whei-Mei Wu for their help with the animal experiments. Special thanks go to the secretaries of the Department of Pharmaceutics (Mrs. Patricia Khan, Ms. Vada Taylor, Mrs. Andrea Tucker, and Mr. James Ketcham) for their technical support. I thank Amparo, Raj, and Sriram for their help and friendship during my internship. I also thank Atul, Rajanikanth, and other graduate students, post-docs and exchange students for their help, the interesting discussions, and their friendship. I am very thankful to my husband, Mark; and my son, Moritz for their love, unconditional support, encouragement, and help during the course of the work. Finally, I would like to thank my parents and sisters for their constant support and encouragement, and their understanding during those 4 years. iv TABLE OF CONTENTS Page ACKNOWLEDGMENTS ................................................................................................. iv LIST OF TABLES............................................................................................................ vii LIST OF FIGURES ........................................................................................................... ix ABSTRACT...................................................................................................................... xii CHAPTER 1 INTRODUCTION ........................................................................................................1 2 LITERATURE OVERVIEW .......................................................................................6 Methylprednisolone in the Treatment of Acute Spinal Cord Injury (ASCI)................6 Nonlinear Pharmacokinetics of Prednisolone.............................................................15 Corticosteroids in the Treatment of Asthma and Allergic Rhinitis ............................18 3 PHARMACOKINETICS OF METHYLPREDNISOLONE IN MOTORCYCLE ACCIDENT VICTIMS WITH ACUTE SPINAL CORD INJURY...........................41 Introduction.................................................................................................................41 Materials and Methods ...............................................................................................42 Results and Discussion ...............................................................................................45 4 A COMPUTER ALGORITHM FOR THE ASSESSMENT OF THE DOSE-DEPENDENT PHARMACOKINETICS AND PHARMACODYNAMICS OF PREDNISOLONE BASED ON LINEAR AND NONLINEAR PROTEIN BINDING ...................................................................................................................57 Introduction.................................................................................................................57 Materials and Methods ...............................................................................................60 Results and Discussion ...............................................................................................66 v 5 ASSESSMENT OF RECEPTOR BINDING AFFINITY OF LOTEPREDNOL ETABONATE AND OTHER NOVEL SOFT STEROIDS USING A COMPETITIVE BINDING ASSAY IN RATS .....................................................74 Introduction.................................................................................................................74 Materials and Methods ...............................................................................................75 Results and Discussion ...............................................................................................78 6 ASSESSMENT OF THE PROTEIN BINDING OF LOTEPREDNOL ETABONATE AND OTHER NOVEL SOFT STEROIDS USING ULTRAFILTRATION ...............................................................................................82 Introduction.................................................................................................................82 Materials and Methods ...............................................................................................83 Results and Discussion ...............................................................................................86 7 PHARMACOKINETICS OF A NOVEL SOFT STEROID AFTER IV ADMINISTRATION TO THE RAT..........................................................................94 Introduction.................................................................................................................94 Materials and Methods ...............................................................................................95 Results and Discussion ...............................................................................................99 8 CONCLUSION.........................................................................................................108 APPENDIX A NONMEM CODE FOR PK MODEL ......................................................................111 B ALGORITHM FOR CUMULATIVE CORTISOL SUPPRESSION ......................114 C FEATURES OF THE COMPUTER ALGORITHM ...............................................123 D DERIVATION OF THE EQUATION OF THE FREE FRACTION IN FULL HUMAN PLASMA..................................................................................................125 LIST OF REFERENCES.................................................................................................128 BIOGRAPHICAL SKETCH ...........................................................................................144 vi LIST OF TABLES Table page 2-1. Pharmacokinetic and pharmacodynamic parameters of inhaled and intranasal corticosteroids ..........................................................................................................22 2-2. Device-dependent bioavailability after inhaled and intranasal administration of corticosteroids ..........................................................................................................27 3-1. Population estimates of the PK parameters for MPHS and MP after high doses in patients with acute spinal cord injury.......................................................................47 3-2. MP standard concentrations—Inter-day precision and accuracy .............................52 3-3. MPHS standard concentrations—Inter-day precision and accuracy ........................52 3-4. MP quality controls—Inter- and intra-batch precision and accuracy.......................52 3-5. MPHS quality controls—Inter- and intra-batch precision and accuracy..................53 4-1. Pharmacokinetic parameter of free prednisolone after IV administration ................62 4-2. Pharmacokinetic parameter of free prednisolone after oral administration ..............63 4-3. Prednisolone plasma concentrations after IV administration of six different doses .69 4-4. Prednisolone plasma concentrations after oral administration of six different doses71 5-1. Average relative receptor binding affinities (n=3) of dexamethasone, loteprednol etabonate, etiprednol dicloacetate and other soft steroids.....................79 6-1. Loteprednol etabonate free fraction in 5% diluted human plasma............................86 6-2. Loteprednol etabonate free fraction in full human plasma........................................87 6-3. Etiprednol dicloacetate free fraction in 5% diluted human plasma...........................87 6-4. Etiprednol dicloacetate free fraction in full human plasma.......................................88 6-5. Compound 929 free fraction in 5% diluted human plasma.......................................88 6-6. Compound 929 free fraction in full human plasma...................................................89 vii 7-1. Compound 929 standard concentrations—Inter-day precision and accuracy for....101 7-2. Compound 929 quality controls—Inter- and intra-batch precision and accuracy...101 7-3. Individual pharmacokinetic parameter estimates of Compound 929 after noncompartmental analysis ....................................................................................103 7-4. Individual pharmacokinetic parameter estimates of Compound 929 after compartmental analysis..........................................................................................104 7-5. Average corticosterone concentrations of each animal in ng/mL (n=2) for each time point........................................................................................................................105 viii LIST OF FIGURES Figure page 1-1. Structure of methylprednisolone hemisuccinate.........................................................3 1-2. Structure of prednisolone sodium