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Gadolinium Deposition from Mri Contrast Agents: Mechanism and Prevention

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Gadolinium Deposition from Mri Contrast Agents: Mechanism and Prevention GADOLINIUM DEPOSITION FROM MRI CONTRAST AGENTS: MECHANISM AND PREVENTION John P. Prybylski A dissertation submitted to the faculty at the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Pharmaceutical Sciences in the Eshelman School of Pharmacy (Pharmacoengineering and Molecular Pharmaceutics). Chapel Hill 2019 Approved by: Michael Jay Philip C. Smith Samuel K. Lai Kim Brouwer Weili Lin © 2019 John P. Prybylski ALL RIGHTS RESERVED ii ABSTRACT John P. Prybylski: Gadolinium Deposition from MRI Contrast Agents: Mechanism and Prevention (Under direction of Michael Jay) Gadolinium (Gd)-based contrast agents (GBCAs) are essential diagnostic drugs used in magnetic resonance imaging (MRI) and have a strong record of safety over the past 20 years. It has recently been shown that trace amounts of Gd remain in the body years after undergoing contrast-enhanced MRI. The risks associated with retained Gd have not been fully elucidated, but tissue Gd concentrations have been associated with toxic sequalae such as nephrogenic systemic fibrosis in patients with low renal function; similar symptoms (skin changes, pain, etc.) have been observed in patients with normal renal function who have been exposed to GBCAs and continue to have high urine Gd excretion months after GBCA dosing. To better understand the risks, mechanisms and causes of Gd deposition, a series of model- informed investigations were carried out, synthesizing in silico, in vitro and in vivo data. First, Gd/GBCAs were modeled in simulated human plasma to determine the distribution of Gd in physiologically relevant fluid and predict the effect of chelators. A compartmental, pharmacokinetic model of Gd/GBCAs was also developed to determine the impact of Gd release from GBCAs on the long- term tissue concentrations of Gd. Next, based on the affinity of Gd for transferrin identified in the human plasma model, the impact of iron status on Gd deposition was assessed; hypoferremia was found to significantly impact the distribution of Gd in the brain, with more Gd accumulating in iron storage regions than in control and hyperferremic rats. Extravasation of injected GBCA was also found to be correlated well with Gd deposition in the brain. Finally, preventing Gd deposition was assessed using either Zn-DTPA (diethyltriamine pentetic acid) or Ca-DTPA; it was determined that the binding kinetics iii of Ca-DTPA for Gd were associated with significantly less deposition when given within 4 h of a GBCA dose. The findings from these studies provide significant insight into the issue of Gd deposition and provide direction for how retained Gd may be removed from the body. iv To my family, friends, mentors and coworkers who supported my efforts and made this experience a cherished one. v TABLE OF CONTENTS LIST OF TABLES ..................................................................................................................................... viii LIST OF FIGURES ..................................................................................................................................... ix LIST OF ABBREVIATIONS ....................................................................................................................... x CHAPTER 1: INTRODUCTION ................................................................................................................. 1 REFERENCES ....................................................................................................................................... 19 CHAPTER 2: SPECIATION OF Gd AND GBCAS IN SIMULATED HUMAN PLASMA. ................... 27 REFERENCES ....................................................................................................................................... 44 CHAPTER 3: BIOKINETIC MODEL OF Gd AND GBCAS. .................................................................. 48 REFERENCES ....................................................................................................................................... 65 CHAPTER 4: THE EFFECT OF IRON STATUS ON Gd DEPOSITION IN THE RAT BRAIN ............ 71 REFERENCES ....................................................................................................................................... 83 CHAPTER 5: EXTRAVASATION OF GBCAS AND RESULTING Gd DEPOSITION ........................ 85 REFERENCES ....................................................................................................................................... 90 CHAPTER 6: THE IMPACT OF Zn-DTPA DOSE TIMING ON Gd DEPOSITION ............................. 91 REFERENCES ..................................................................................................................................... 104 CHAPTER 7: IMPACT OF DTPA CHELATION KINETICS ON Gd DEPOSITION. .......................... 107 REFERENCES ..................................................................................................................................... 115 CHAPTER 8: PERSPECTIVE AND CONCLUSIONS ........................................................................... 117 REFERENCES ..................................................................................................................................... 122 APPENDIX 1: OPTIMIZING PREDICTED FORMATION CONSTANTS FROM THE BROWN-SYLVA METHOD ............................................................................................. 125 APPENDIX 2: OPTIMIZATION PROCEDURES FOR THE Gd/GBCA BIOKINETIC MODEL ........ 127 vi APPENDIX 3: A CASE OF PROLONGED GADOLINIUM IN URINE UP TO 1000 DAYS AFTER LAST MRI: CALCULATING EFFECTIVE NUMBER OF CHELATOR DOSES ......................................................................................................................... 129 REFERENCES ..................................................................................................................................... 137 APPENDIX 4: THE IMPACT OF EXTRAVASATION ON SIMULATED GBCA BIOKINETICS .... 139 REFERENCES ..................................................................................................................................... 141 APPENDIX 5. FITTING GBCA TRANSMETALLATION KINETICS ................................................ 142 REFERENCES ..................................................................................................................................... 145 vii LIST OF TABLES Table 2.1. Normal values for speciation of selected endogenous metals in healthy patients and those in the simulation. .............................................................................................. 35 Table 2.2. Speciation of different gadolinium-based contrast agents at 1 mM in human serum. ............... 40 Table 3.1. Transformations applied to extracted data to normalize values to those that may be observed in a patient after one standard human dose................................................. 53 Table 3.2. Number of data points and time range covered in extracted studies in normal humans and animals. ...................................................................................................... 56 Table 3.3. Regression results for the attempted model fits ......................................................................... 57 Table 3.4. Model diagnostics for each estimation approach for each tissue and ligand. ............................ 59 Table 4.1. The correlation matrix for gadolinium concentration in each organ in the 3-week washout group stratified by dietary iron levels. ................................................................... 79 Table 6.1. Impact of time of chelation treatment on Gd concentration in various tissues following GBCA administration. ....................................................................................... 96 Table 7.1. Regression results for the simple, exponential processing step and for fit to the final ODE model. ........................................................................................................... 111 Table A1.1. The summary adjustment results following Monte Carlo cross-validation are listed for each adjustment ......................................................................................... 126 Table A3.1. Regression results for the fit of 24-hour urine gadolinium data under different conditions. 132 viii LIST OF FIGURES Figure 1.1. The first zheumatogram .............................................................................................................. 2 Figure 1.2. Hyperintesity in the dentate nucleus (lower circled region) in T1-weighted MR imaging (left) not observable in T2-weighted imaging (right) ......................................... 3 Figure 1.3. The structures of all GBCAs currently marketed in the United States. ...................................... 5 Figure 2.1. Percent intact of different GBCA formulations at physiologically relevant concentrations according to the simulated plasma model. ............................................................ 36 Figure 2.2. The speciation of Gd released by GBCAs among general components of plasma. ................. 36 Figure 2.3. Relative amount of released Gd bound to transferrin ............................................................... 37 Figure 2.4. Calculated conditional stability constants for each GBCA ...................................................... 37 Figure 2.5. The influence of excess ligand on the amount of GBCA
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