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Intranasal and Rectal Diazepam for Rescue Therapy: Assessment of Pharmacokinetics and Tolerability a Dissertation Submitted to T

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Intranasal and Rectal Diazepam for Rescue Therapy: Assessment of Pharmacokinetics and Tolerability a Dissertation Submitted to T INTRANASAL AND RECTAL DIAZEPAM FOR RESCUE THERAPY: ASSESSMENT OF PHARMACOKINETICS AND TOLERABILITY A DISSERTATION SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL OF THE UNIVERSITY OF MINNESOTA BY VIJAY DEEP IVATURI IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY ADVISER: JAMES. C. CLOYD DECEMBER 2010 © VIJAY DEEP IVATURI 2010 ACKNOWLEDGEMENTS This thesis was carried out at the Center for Orphan Drug Research, Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, United States. I would like to thank the following persons who have all contributed to this thesis and have been important to me throughout my time as a research student; My supervisor/adviser Professor James Cloyd for giving me the opportunity to join the Orphan Drug Research group. Thank you for sharing your vast knowledge and enthusiasm about research. Thanks for all the care and consideration that you and Mrs. Cloyd have always shown and for letting me experience a family away from home. I also appreciate you letting me pursue my personal interest in the application of Pharmacometrics into our research projects and for letting me take a break from my studies to go to GlaxoSmithKline and try a world outside the university. My second committee member Dr. Robert Kriel for showing interest in my work and always questioning the usability and necessity of things and for also being the first to give comments back on reports and manuscripts. Thanks for sharing your expert clinical knowledge and giving me an opportunity to do a clinical clerkship at Hennipen County Medical Center and Gillette Children’s Hospital. The chair of my committee Professor Richard Brundage for always being positive about my work and also teaching me NONMEM with a lot of patience. Without your support and encouraging words I would probably be doing something else today. I will dearly miss the Pharmacometrics discussion groups. My third committee member Dr. Bimal Malhotra for always listening to, and encouraging my ideas. Your lectures at St. John’s University on pharmacokinetics gave me the push I needed to switch fields from drug delivery to clinical pharmacology. Thanks for your recommendations, and for helping me choose the program at Minnesota. i Most of all, thank you for serving as a committee member and accommodating to date changes even with your packed schedule in the industry. Usha Mishra, for all the expertise and help you provided in the bionalytical lab. Dr. Ginny Schmidth, for being such a lovely mentor during my summer internship at GSK. Thanks for the wonderful opportunity to work on an interesting project and teaching me the survival skills in a corporate environment. Carol Ann Dickinson, for always being helpful with department related issues and of course as it is said, for being the “Mother of the Department”. Nancy McClanahan, for helping with all the administrative issues at CODR. Thanks for keeping the coffee stocks loaded, it really helped us be more efficient. Dr. Ramaiha Muthyala for your motivating talks while at CODR about aiming high and to pursue the road not taken. Drs. Tim Tracy, Bob Straka & Rory Remmel, for sharing your expert knowledge during the weekly readings. I learnt quiet a lot from all of you. Annie, for being such a lovely office mate, for ‘almost’ sharing a birthday and always keeping the office nice and warm. I will miss the discussions on new movie releases and television shows. Best wishes on starting a family. Amit for being a good friend and housemate, and helping me scrape through many of the grueling coursework that we took together. Our discussions significantly improved my Pharmacometrics knowledge. Senior members of the Pharmacometrics group; Manisha, Varun & Kyle for listening to my frustrations and patiently discussing problems related to general concepts of modeling, and helping with coding in NOMEM and R. ii The other members of the Pharmacometrics group; Hyewon, Akshanth, Chaitali, Jia, Ahmed, Gada, Lisa and Heather for being such a lovely group. Learning together with you guys was a great experience and I will miss all the animated discussions of the group. To my Family and Friends; Mom, thanks for always believing and letting me pursue my interests. Thank you for sharing your simple but important lesson with me just before I started college in Manipal, it is and will be of immense help always. Dad, thanks for always being proud of me and always being ready to help whenever I needed something. My brothers and sisters-in-law, thanks for being such good friends and supporting me in times of need. You all played a huge role in my achievements till date. Chaganti’s, thanks for all the lovely Christmas parties and delicious meals. I can’t wait to play some more ‘literature’ with you all again. My dear friends Maansi, Sumit & Vishak; Thanks for always being there whenever I had to talk to someone. You have always been close even though we lived far apart. Finally, thanks to all my past and present colleagues who were a part of my journey through this phase of my career. iii DEDICATION To all my Teachers for their belief in me & My family for their love and unending support iv ABSTRACT The use of rectal diazepam has improved the management of acute repetitive seizures (ARS) outside a health care facility. Two placebo controlled trials have shown that rectal administration of diazepam is safe and effective for treatment of this condition. Diastat® is the only FDA approved treatment for ARS in the United States. Although some older children and adults are willing to use Diastat®, many patients in these age groups as well as physicians and caregivers object to the route of administration and instead use other therapies not approved for this purpose, receive no treatment, or use emergency medical services or acute care systems. We developed and evaluated three nasal spray formulations of diazepam which can be easily administered with rapid absorption characteristics intended as an alternative to rectal administration. One formulation used a supersaturated glycofurol based co-solvent system while the remaining two (Nas-A & Nas-B) used microemulsion based co-solvent systems. These formulations were studied for their pharmacokinetics and tolerability in healthy adult volunteers. Data from these studies were then compared to the pharmacokinetics after rectal administration using both model-based analysis (NONMEM) and graphical methods. The primary finding from this work was that, only the microemulsion-based formulations, particularly Nas-B could be used for further development as the glycofurol formulation was not well tolerated by subjects. The pharmacokinetic profiles after intranasal administration were associated with high variability. However, we are able to show that the dose-normalized partial area under the curve (AUC - an exposure parameter) after nasal administration, at times when the drug concentrations are most important, are 60-80 % of that when given via the rectal route. Given the ease and social acceptability of nasal administration compared to rectal, equivalent exposures can be easily attained by giving a second nasal dose, and we thus conclude that intranasal diazepam is a feasible and preferable alternative to rectal diazepam in the management of v ARS outside a hospital. This work also provides some recommendations for future studies in the development of an intranasal product. vi TABLE OF CONTENTS Acknowledgements ……………………………………………………………………… i Dedication .………………………………………………………………………………iv Abstract ….…………………………………………………………………………….....v Table of Contents ..……………………………………………………………………...vii List of Tables ….....……………………………………………………………………...xii Table of Figures ....…………………………………………………………………..…xiv CHAPTER 1 INTRODUCTION................................................................................. 1 1.0 Epilepsy ................................................................................................. 2 1.0.1 Disease State........................................................................................... 3 1.0.2 Seizure Classification ............................................................................. 3 1.0.2.1 Partial seizures ........................................................................................ 4 1.0.2.2 Generalized seizures ............................................................................... 4 1.0.2.2.1 Tonic–clonic or major motor seizures ................................................... 4 1.0.2.2.2 Absence or petit mal seizures ................................................................ 4 1.0.2.2.3 Atypical absence seizures ...................................................................... 5 1.0.2.2.4 Atonic or drop seizure ........................................................................... 5 1.0.2.3 Febrile seizures ....................................................................................... 5 1.0.2.4 Status epilepticus .................................................................................... 6 1.0.2.5 Seizure Emergencies .............................................................................. 6 1.1 Seizure Emergencies ............................................................................. 7 1.1.1 Acute Repetitive Seizures (ARS) / Seizure Clusters .............................. 8 vii 1.1.1.1 Mechanism of ARS ................................................................................ 9 1.1.1.2 Definitions of Seizure Clustering ........................................................
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