Curriculum Vitae
`
`Fatemeh Akhlaghi, Pharm.D., Ph.D.
`
`Summary: I am a pharmaceutical scientist with expertise in clinical pharmacology, translational
`sciences, drug metabolism, pharmacogenomics and pharrnacokinetic/pharmacodynamic (PKPD)
`modeling. My research goal is to understand the sources of variability in drug disposition and
`effect specifically in patients with diabetes mellitus or non-alcoholic fatty liver disease (NAFLD).
`The long-term goal is to devise personalized medicine these disease state. I am proficient in design
`and implementation of clinical pharmacokinetic studies, quantification of drug concentration and
`metabolites using LC-MS/MS and data analysis by standard or population pharmacokinetics
`methods. Characterization of expression and activity of drug metabolism enzymes and transporters
`ex vivo or in vitro is another area of research practiced in my laboratory. diabetes mellitus on drug
`disposition,
`drug
`development
`in
`alcoholism and
`therapeutic
`drug monitoring of
`immunosuppressive agents in organ transplant recipients.
`In addition, I am the director of the
`graduate program in Pharmaceutics and Pharmacokinetics and Principal Investigator on two NIH
`grants.
`
`Personal Information
`
`Date of Birth: November 18‘“, 1966
`Marital Status: Married with a 24-year old daughter
`Residency Status: Naturalized Citizen of the United States
`
`Work Address
`
`Department of Biomedical and Pharmaceutical Sciences
`495A College of Pharmacy, 7 Greenhouse Road
`University of Rhode Island
`Kingston, RI 02881
`Phone: (401) 874 9205 /Fax: (401) 874 5787
`Email: fatemeh@uri.edu
`litt
`:ix‘web.urinedu:r harmac fresearchfakhla lhiz’
`Departmental Website URI:
`
`httpx’fakhlaghilabcom/
`Laboratory Website URI:
`hugs:ffvivo.brown.cdufdisplavflhkhlagh
`Website Brown University:
`Google Scholar:
`htt s:/fscholar. 100 rle.com/citations?user=wdnBYOAAAAAJ&hl=en
`
`Linkedin site:
`littpflwww.linkedin.00mfinfakhlaghi
`ORCID ID: orcid.org
`0000-0002-3946-7615
`
`EDUCATION
`
`1984-1990
`Project title:
`Major Professor:
`
`Pharm.D.
`University of Mashhad, Iran
`Use of CD4 to CD8 ratio as a marker for kidney transplant rejection
`Behrouz Nikbin M.D.
`
`1992-1997
`Project title:
`
`Ph.D. in Pharmaceutical Sciences
`University of Sydney, Australia
`Cyclosporine distribution in cardiopulmonary transplant recipients
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`Major Professors: Kenneth F. Brown Ph.D. and Anne M. Keogh M.D.
`
`July 2014-
`
`July 2014-
`
`July 2011-
`
`July 2010-
`
`2006-2010
`
`2001-2006
`
`1998-2001
`
`EMPLOYMENT HISTORY
`
`University of Rhode Island
`Pharmaceutics
`
`Ernest Mario Distinguished Chair in
`
`Brown University Medical School Adjunct Professor of Medicine
`
`University of Rhode Island
`
`Full Professor
`
`Brown University Medical School Adjunct Associate Professor
`
`University of Rhode Island
`
`Associate Professor with Tenure
`
`University of Rhode Island
`
`Assistant Professor (Tenure Tack)
`
`University of Cambridge, UK.
`
`Senior Clinical Scientist
`
`(Advisor: Andrew K Trull Ph.D.; Funded by Novartis, Roche Laboratories and Papworth
`Hospital Research Trust)
`
`1996-1998
`
`University of Sydney, Australia
`
`Post-Doctoral Research Associate
`
`(Advisors: Kenneth F. Brown PhD. and Andrew J McLachlan Ph.D.; Funded by Novartis and
`Janssen Cilag Australia)
`
`FURTHER TRAINING
`
`March 13, 2016
`Design and Analysis of Quantitative Proteomic Experiments: Introduction to Statistical Methods
`and Practical Examples using Skyline, one-day workshop part of Human Proteomics Organization
`meeting in Boston, MA
`
`July 6-10, 2015
`Incorporating Population Variability into Mechanistic
`Model-Based Drug Development:
`Prediction of PK and Modelling PK-PD
`A course on Simcyp, Certara Corporation
`
`Aug 5-6, 2014
`Transporters in Drug Discovery and Development
`University of Rhode Island
`
`Jan-March, 2013
`Hands on data manipulation using R
`Instructor: Dr. Kaori Ito, Pfizer Groton
`
`May 1-5, 2012
`Fisher / Shafer NONMEM Course
`
`An Intermediate to Advanced NONMEM course With PLT tools
`
`Bethesda, MD
`
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`March 19-21, 2012
`The Introductory GastroPlusTM Simulation and Modeling Workshop
`Cambridge, MA.
`
`March 29-31, 2011
`Triple Quadrupole System Training using Analyst® Software for Quantitation
`AB Sciex, Framingham, MA.
`
`October 4, 2009
`Phoenix NLME - A Next Generation Tool for Population PK/PD Analysis
`Instructor: Dan Weiner, Pharsight Corporation.
`
`September 16, 2006
`Course in Pharmacokinetic/Pharmacodynamic Modeling
`Instructors: Drs William J. Jusko and Jogarao Gobburu.
`
`September 12-14, 2005
`A three-day hands-on course on “Wings for NONMEM Population Pharmacokinetics Modeling”;
`Instructors: Drs Nick Holford and Dianne Mould
`
`Also organized the course with Dr. Sara Rosenbaum.
`July 26-30, 2004
`
`A weeklong hands-on course entitled “Molecular Genetic Methodologies for Pharmaceutical
`Scientists”; Department of Pharmaceutical Sciences, University of Buffalo;
`Instructor: Dr. Dan Brazeau.
`
`June 2002
`
`A three full days hands-on course “Operator’s Training on Sciex AP12000 Liquid Chromatography
`Mass Spectrometer” University of Rhode Island, also organized the course.
`Instructor: Dr. Bill Sawyers, Applied Biosystems.
`
`September 27-29, 1999
`Beginning level short course on “Population Pharmacokinetics using NONMEM Computer
`Program”
`Instructors: Drs Lewis Sheiner and Stuart Beal; Uppsala Sweden.
`
`January 9-15, 1999
`“A course in Pharmacokinetic and Pharmacodynamic Modeling using WinNonlin” one credit
`point; Department of Clinical Pharmacology, Karoliniska Institute, Stockholm, Sweden;
`Instructor: Dr. Ole Borga.
`
`December 7-22, 1998
`“A course in Pharmacokinetic and Pharmacodynamic with Clinical Applications”; four credit
`points; Department of Clinical Pharmacology, Karoliniska Institute, Stockholm, Sweden;
`Instructors: Drs Gunnar Alvan, Ole Borga, Johan Gabrielsson, Lars Gustafsson.
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`HONORS AND AWARDS
`
`1992
`1993-96
`2002
`2006
`2008
`2010
`
`Levy Maill Pattinson Award, Faculty of Pharmacy, Uni. of Sydney
`Faculty of Pharmacy Postgraduate Scholarship, Uni. of Sydney
`University of Rhode Island New Faculty Development Award
`Outstanding Intellectual Property Award, University of Rhode Island
`Paul-Ehrlich Magic Bullet-Award 2008, Numberg Germany
`Outstanding Intellectual Property Award, University of Rhode Island
`
`PROFESSIONAL SOCIETY MEMBERSHIP
`
`1990-present
`1993-1998
`
`1993-1998
`1997-2001
`1998-2001
`1996-present
`
`The Medical Council of Iran (Registered Pharmacist)
`Australasian Society for Clinical and Experimental Pharmacology and Toxicology
`(ASCEPT)
`Australasian Pharmaceutical Science Association (APSA)
`International Society of Heart and Lung transplantation (ISHLT)
`Transplantation Society
`International Association of Therapeutic Drug Monitoring and Clinical Toxicology
`(IATDM&CT)
`1997—present American Association of Pharmaceutical Scientists (AAPS)
`2001-present American Association of Colleges of Pharmacies (AACP)
`2008-present American Society for Clinical Pharmacology and Therapeutics (ASCPT)
`
`CONSULTING ACTIVITIES
`
`1996
`
`Physicochemical characteristics of ingredients of an antacid suspension,
`consultant for Park Davis Pharmaceuticals in collaboration with Dr. Elizabeth
`
`2001-2003
`
`2003
`
`2005
`
`Gipps, University of Sydney
`1997-1998 Droplet size determination of nebulized solutions of Salbutamol and Ipratropium
`Bromide using Marple - Miller cascade impactor, in collaborating with Dr. Kim
`Chan, University of Sydney
`Pharmacokinetics of intravenous immunoglobulin (IVIG), I have analyzed the
`pharmacokinetic data from several phase III studies conducted by Bio Products
`Limited, UK
`‘
`Member of Mycophenolic Acid TDM Advisory Board (Opticept clinical trial, an
`800 patient trial conducted by Roche Laboratories to evaluate the need for
`mycophenolic acid therapeutic drug monitoring)
`Consulting on a case study conducted at the Department of Emergency Medicine,
`RI hospital on the elimination of carboxy hemoglobin
`Expert witness
`in a personal
`injury case involving cyclosporine generic
`substitution and risk of organ rejection
`Expert witness in a patent dispute case between two major pharmaceutical
`companies
`
`2005-2007
`
`2007
`
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`pharmacodynamic modeling
`and
`Pharmacokinetic
`cynomongolus monkeys, Millennium Pharmaceuticals
`Pharmacokinetic consultant for a clinical trial on the intra-nasal use of ketamine
`
`of
`
`bortezomib
`
`in
`
`2008-2009
`
`2007-2010
`
`2011
`
`2014
`2014
`2016-2017
`
`2017-
`
`in children with laceration, Department of Emergency Medicine, Hasbro Children
`Hospital, Providence, RI.
`Consultant on concentration—projection of a modified release tablet by two
`different manufacturers.
`
`Expert witness for a non—infringement trial for two Canadian companies
`Consultant on bioequivalence studies on a generic versus a brand name drug
`Consultant on a patent dispute case involving a combination anti-hyperglycemic
`agent
`Consultant on a patent dispute case involving projection of pharmacokinetic
`parameters of controlled release formulations
`
`DATE
`
`PRESENTATION TITLE/LOCATION
`
`INVITED PRESENTATIONS
`
`Nov 1999
`
`“Pharmacokinetics of cyclosporine in patients receiving metabolic inhibitors”
`Invited speaker at PKUK99 meeting, Oxford, UK.
`
`Aug 16 2001
`
`“Clinical pharmacology of immunosuppressive agents” Lecture to the
`Nephrology Residents, Department of Nephrology, Brown University Medical
`School, Providence, RI.
`
`Oct 1 2001
`
`Oct 23 2001
`
`“Novel strategies for monitoring immunosuppressive agents” invited speaker at
`the Department of Pediatrics Nephrology and Transplantation, the Boston’s
`Children Hospital, University of Harvard Medical School, Boston, MA.
`
`to the Heart
`recipients” Seminar
`“Monitoring cardiothoracic transplant
`Transplant Group, the Brigham and Woman’s Hospital, University of Harvard
`Medical School, Boston, MA.
`
`Jan 25 2002
`
`“Novel strategies for monitoring immunosuppressive agents” Seminar to
`Kidney Transplantation Services, Rhode Island Hospital, Providence, RI.
`
`Jul 11 2003
`
`“Pharmacokinetics and pharmacodynamics of immunosuppressive agents” oral
`presentation at RI-BRIN annual retreat, Alton Jones Campus, RI.
`
`May 20 2004
`
`Speaker at the workshop “Hot and alternative research funding” Title: How to
`Get Funding from the Industry, University of Rhode Island, Kingston, RI.
`
`Apr 7 2005
`
`in diabetic patients”
`agents
`immunosuppressive
`“Pharmacokinetics of
`Presentation to the Transplant Services, RI Hospital, Providence, RI.
`
`Jan 25 2006
`
`“Pharmacokinetics and —dynamics of immunosuppressive agents” Center for the
`New Stem Cell Biology Visiting Professors Seminar Series, COBRE program,
`Roger Williams Hospital, Providence, RI.
`
`May 24 2006 Poster Judge at the Joint RI-COBRE symposiums, Providence, RI.
`
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`May 312007
`
`“Transplant
`at
`invited speaker
`transplant pharmacology”
`“Review of
`Pharmacology: Keys
`to Medication Management
`in Organ Transplant
`Recipients”; Pharmacist CE program, Providence, RI.
`
`Sept 11 2007 Research presentation “pharmacokinetic of immunosuppressive agents in
`diabetic patients” Millennium Pharmaceuticals, Boston, MA.
`
`Oct 2 2007
`
`“Novel monitoring methods for immunosuppressive agents PKPD” Research
`presentation at College of Pharmacy, University of Kentucky, Lexington, KY.
`
`Oct 24 2007
`
`“Immunosuppressive agents PK/PD and diabetes mellitus” Visiting professor
`program, Department of Pharmacology and Experimental Therapeutics, Tufts
`University School of Medicine, Boston, MA.
`
`Jan 2 2008
`
`“Effect of diabetes mellitus on drug metabolism and transporter” Hallett Center
`for Diabetes and Endocrinology Disorders, Brown University, Providence, RI.
`
`July 25 2008
`
`“Pharrnacokinetics and —dynamic modeling of bortezomib in cynomonglous
`monkeys” Department of Clinical Pharmacology, Millennium Pharmaceuticals,
`Cambridge, MA.
`
`Sept 3 2008
`
`Oct 5 2008
`
`“Introduction to pharmacokinetic/pharmacogenomics modeling and application:
`a Velcade® case study” R&D presentation, Millennium Pharmaceuticals,
`Cambridge, MA.
`
`“Effect of diabetes mellitus on pharmacokinetics and pharmacodynamics of
`immunosuppressive agents: ciclosporin, tacrolimus and mycophenolic acid”
`Invited speaker at EHRLICH II, 2nd World Conference on Magic Bullets,
`Numberg, Germany.
`
`May 20 2009
`
`“Application of clinical pharmacology to improve the quality of use of
`medicines in diabetes and transplantation” invited speaker at Division of
`Clinical Pharmacology, Johns Hopkins University, Baltimore, MD.
`
`May 2 2010
`
`Sept 7 2010
`
`“Drug monitoring in distinct patient populations; pharmacokinetic differences
`between transplant recipients of different ethnicities”, invited speaker at Sunrise
`symposium, the American Transplant Congress, May 2010, San Diego, CA.
`
`“Diabetes, reduced CYP3A4 activity and the possible role of statin lactone in
`statin induced myopathy”; presentation at
`the department of cardiology,
`Hartford Hospital, Hartford, CT.
`
`Sept 28 2010
`
`in an FDA workshop on “Pharmacodynamic and
`Invited participant
`Pharmacogenomics biomarkers in solid organ transplantation”, Food and Drug
`Administration, White Oak Campus, MD.
`
`Dec 14 2010
`
`of
`pharmacodynamics
`and
`biotransformation
`altering
`“Diabetes
`at
`the Department of
`speaker
`agents”;
`Invited
`immunosuppressive
`Pharmaceutical Sciences, University of Colorado Health Science Center,
`Anschutz Medical Campus Aurora, CO.
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`Mar 23 2011 Diabetes and side effects of statins, American Heart Association Friends of
`Heart Luncheon, Center for Biotechnology and Life Sciences (CBLS) building,
`University of Rhode Island
`
`Oct 8 2011
`
`Influence of diabetes mellitus on the disposition of immunosuppressive agents
`and statins, PDM department, Pfizer Center Research, Groton, CT.
`
`Aug 28, 2012 Impact of protein binding on drug disposition and action, College of Pharmacy,
`University of Technology, Sydney, Australia via Video conferencing.
`
`Oct 22, 2012 Altered disposition of xenobiotics by diabetes mellitus, Division of Clinical
`Pharmacology, Johns Hopkins Medical Institute, Baltimore, MD.
`
`Aug 8, 2013
`
`Altered disposition of xenobiotics by diabetes mellitus and fatty liver, College
`of Pharmacy, University of Houston, Tx.
`
`pharmacodynamics of
`and
`pharrnacokinetics
`on
`Nov 18,2013 Effect of diabetes
`immunosuppressive agents, Division of Transplantation, Methodist Hospital,
`Houston, Tx.
`
`Mar 13, 2014 AACP Academic Research Fellows Program; Model of Team Science IV:
`Collaboration between academia, government, industry supported by NCATS;
`Rockville, MD.
`
`Aug 7, 2014
`
`Invited Speaker at “Pharmacogenomic Interplay in Biotransformation and
`Pharmacokinetics”; Pharmacokinetic consequences of metabolic syndrome;
`University of Rhode Island
`
`Mar 12, 2015
`
`Invited Speaker at the 30th Annual Seminar by the Sea; Northeast Regional
`Continuing Education Conference for Pharmacists
`
`“Statin Interactions: Food, Supplements and Other Drugs”
`
`July 13, 2015 AACP Academic Research Fellows Program; Model of Team Science IV:
`Collaboration between academia, government, industry supported by NCATS;
`Potomac, MD.
`
`Oct 20, 2015
`
`Presentation of the result of phase 1b of PF-05190457 study in subjects with
`alcohol use disorders; NIH Clinical Center, Bethesda, MD.
`
`Nov 5, 2015 Workshop leader on Mechanisms of Drug-Drug Interactions; International
`Congress of Quality, Safety and Rationale Use of Drugs, University of Mashhad,
`Mashhad, Iran
`
`Nov 6’ 2015
`
`“Clinical Pharmacology and Therapeutic Monitoring of Immunosuppressive
`Agents” International Congress of Quality, Safety and Rationale Use of Drugs,
`University of Mashhad, Mashhad, Iran
`
`Feb 2, 2016
`
`Invited speaker in Connecticut Mass Spec Discussion group
`
`Title: Pharmacokinetic Consequences of Metabolic Syndrome: Challenges and
`Opportunities for Proteomic Mass Spectrometry
`
`Dec 6, 2016
`
`Invited speaker, Pfizer Cambridge
`
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`Title: Pharmacokinetics Consequences of Type 2 Diabetes (T2DM) and Non
`Alcoholic Fatty Liver Disease (NAFLD)
`
`Feb 8, 2017
`
`Invited speaker, department of gastroenterology, Beth Israel Deaconess Medical
`Center
`
`2001-present
`2003-present
`2003—present
`2002
`
`2004
`
`2006-present
`2006-present
`2007-present
`2009
`
`2009
`
`2010-present
`2010-
`
`201 1-
`
`2013-
`
`2016—
`
`2016-
`
`2016-
`
`2016-
`
`2016
`
`AD HOC REVIEWER FOR SCIENTIFIC JOURNALS
`
`British Journal of Clinical Pharmacology
`Clinical Pharmacokinetics
`
`Journal of Chromatography B
`Pharmacoeconomics
`
`Transplantation
`Journal of Pharmacology and Experimental Therapeutics (JPET)
`Clinica Chemica Acta
`
`Clinical Pharmacology and Therapeutics
`European Journal of Clinical Pharmacology
`Liver Transplantation
`British Journal of Pharmacology
`Journal of Pharmaceutical and Biomedical Analysis
`European Journal of Medicinal Chemistry
`Lancet
`
`New England Journal of Medicine
`Current Drug Metabolism
`Pharmacotherapy
`Alcohol and Alcoholism
`
`Medical Science Monitor
`
`JOURNAL EDITORIAL BOARD
`
`2013-present
`2015—present
`2014-present
`
`Clinical Pharmacokinetics
`
`Journal of Pharmaceutics and Drug Research
`Journal of Research in Pharmacy Practice
`
`GRANT REVIEWS
`
`2007
`
`2009
`
`2013
`
`2013-present
`
`2014 April
`2014 June
`
`2014 August
`2015 March
`
`Department of Defense, Chemical and Biological Defense Basic, Research
`Program
`The Czech Science Foundation, Czech Republic (GACR)
`National Science Center, Poland
`Qatar National Research Foundation (QNRF)
`Reviewing 2-3 grants in each grant cycle
`NIAID special emphasis panel; ZAI] PA-I M1, ad hoc reviewer
`XNDA study section, ad hoc reviewer
`ZTRl CI-6 (01) review of NCATS X02 grants
`ZTRl CI-6 (02); Study section for review of NCATS UH2/UH3 grants
`
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`2015 Oct
`
`2016 May
`2016 June
`
`2017 Jan
`
`2017 June
`
`CIDO Study section, ad hoc reviewer, Chicago, Illinois
`ZAIl-BDP-I-M4 study section, mail in reviewer
`BCHI study section, mail in reviewer
`ZAIl PA-I (M2) 1 NIAID R34 review study section
`Nominated to be a standing member of Clinical and Integrative Diabetes
`and Obesity [CIDO] Study Section
`
`TEACHING RESPONSIBILITIES
`
`BPS403
`
`Pharmacokinetics I (Basic Pharmacokinetics)
`
`PHC427
`
`4‘h year Interactive Learning
`
`Drug metabolism (experimental)
`
`2002-2004, Team-
`taught (50%)
`
`2002, Sole instructor
`
`2003, Team taught
`
`Drug development
`Pharmacokinetics in various phases ofdrug development
`
`2005-now, Team taught
`
`Pharmacokinetics II (Applied Pharmacokinetics)
`
`Experimental techniques in biomedical sciences
`Use ofmass spectrometry in quantitative analysis
`
`2001- now, Sole
`instructor
`
`2004-now, Team taught
`
`Pharmacy practice laboratory II
`
`2002-now, Team taught
`
`Topics in drug metabolism
`Pharmacokinetics and drug-drug interaction studies
`
`2005, 2007, 2011, 2013,
`2015, Team taught
`
`BMS540
`
`BPS502
`
`BPSSO4
`
`BPS525
`
`PHP516
`
`BPS530
`
`PHC5 97
`
`5th year Interactive Learning (1 section)
`
`BPS693/
`
`Graduate seminar
`
`694
`
`APS670
`
`Advanced pharrnacokinetics
`
`2003- 2007, 2015, Sole
`Instructor
`
`2002-2004, 2015-
`
`2001, 2003, 2009, 2014,
`2016 Sole instructor
`
`Average student evaluation ofteaching score: 4.5 out of5 in didactic courses
`
`SERVICE ACTIVITIES IN THE UNIVERSITY OF RHODE ISLAND
`
`2005
`
`URI sabbatical review committee
`
`2008-201 1
`
`2009-current
`2007-2008
`
`2009
`
`2010
`
`URI president appointee at the “Intellectual Property Committee (IPC)”
`Member of “URI Institutional Review Board (IRB)”
`Member of search committee for “Assistant Vice President for Research,
`Intellectual Property Management and Commercialization”
`Member of search committee for “Technology Transfer Specialist”
`Member of search committee for biostatistics faculty in the department of
`Computer Science and Statistics
`
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`2014
`
`Member of search committee for biostatistics faculty in the department of
`Computer Science and Statistics
`2015-current Member of faculty Senate, URI
`
`Service Activities in College of Pharmacy (COP) or
`Department of Biomedical and Pharmaceutical Sciences (BPS)
`2006-current Member of research and graduate studies committee, COP
`2010-2013
`Program assessment committee, Vice chair, COP
`2007-08
`Member of ad-hoc promotion and tenure standards committee, BPS
`2003, 05, 07 Member of various faculty search committees, BPS
`2010
`Search committee for two pharmaceutics positions, BPS
`2011
`Member of search committee for Pharmacogenomics faculty, BPS
`2010-2011
`Coordinator of INBRE seminar series, college of pharmacy
`2012
`Member of search committee for BPS departmental chair
`2012-
`Coordinator of College of Pharmacy College Wide Seminar series
`2013-
`Chair of liver and metabolic disorders working group, COP
`2013-
`Chair of faculty development committee, BPS
`2013
`Chair of promotion and tenure committee, COP
`2013
`Chair of full professors committee, COP
`2013
`Member of medicinal chemistry search committee, BPS
`2014
`Chair of Pharmaceutics faculty search committee, BPS
`2015
`Member of Pharmacogenomic faculty search committee, BPS
`2016
`Chair of two faculty searches in pharmaceutics
`2017
`Chair of search committee for Assistant/Associate Professor on Pharmaceutics
`
`2012
`
`2014
`
`2016
`
`Sept 14, 2016
`
`ORGANIZATION OF SCIENTIFIC CONFERENCES
`
`Co-chair of 1St International Conference on Frontiers in Pharmaceutical
`
`Sciences: Global Perspectives; September 28-30, 2012
`Member of organizing committee for Pharmacogenomic Interplay in
`Biotransformation and Pharmacokinetics, August 7th & 8th, 2014
`Member of organizational committee for Boston Society 2016 Applied
`Pharmaceutical Analysis conference
`Session chair, Non—P450 Metabolism / Electron Pushing / Unusual Metabolism in
`2016 Applied Pharmaceutical Analysis conference
`
`STATEMENT OF RESEARCH
`
`My research program is aimed at improving the quality of use of medications by means of
`identifying sources of variability in dose-concentration and concentration-effect relationships.
`Identification of new or improved biomarkers for drug effect is also another aim of this research.
`This type of research is usually identified as a branch of “Clinical/translational Pharmaceutical
`Sciences” within pharmacy schools but also is known as “Clinical Pharmacology” in the medical
`schools. During the drug development process (Phase I-III), Food and Drug Administration of
`United States (FDA) and other regulatory agencies avidly scrutinize a new agent for its safety and
`effectiveness; however many aspects of a new drug including side effects or drug-drug interactions
`are only discovered after the new drug is prescribed to a large number of patients. My research
`effort is focused on the evaluation of safety and effectiveness of post-marketed drugs (Phase IV)
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`with an emphasis on the immunomodulators. The three main objectives of my research program
`include:
`
`II.
`
`III.
`
`Several projects are currently underway aiming to:
`I.
`To characterize the effect of diabetic mellitus on immunosuppressive agents’ disposition
`and concentration-effect relationship in kidney transplant recipients.
`To study enzyme activity and protein expression for major phase I and phase II drug
`metabolizing enzymes in diabetic and non-diabetic tissues.
`To study the disposition of statin lipid lowering agents in type 2 diabetic patients and to
`identify factors (i.e. CYP3A activity, genetic polymorphism, pro-inflammatory cytokines)
`in predisposing a diabetic patient to statin related myopathy.
`To validate the use of saliva as a non-invasive specimen for therapeutic drug monitoring
`of immunosuppressive agents.
`Development of A Novel Compound for Alcoholism Treatment: a Translational Strategy
`
`IV.
`
`V.
`
`Other research areas include utilization of iodinated contrast media agents for precise assessment
`of kidney function and development of better/alternative dosage forms.
`I have elaborated on each
`of these areas in the following paragraphs:
`
`(i)
`
`To characterize the effect of diabetic mellitus on immunosuppressive agents’
`disposition and concentration-effect relationship in kidney transplant recipients.
`
`A kidney allograft transplant is the ultimate method of treatment for End Stage Renal Disease
`(ESRD). To prevent rejection, a transplant recipient will remain dependent on a life-long treatment
`with several immunosuppressive agents with unpredictable pharmacokinetics and numerous side
`effects. Approximately 30% of all kidney transplant recipients in the United States are diabetics
`before transplant and 15-20% develop new onset diabetes post-transplant (NoDAT). Data from
`UNOS and USDRS suggest that both graft and patient survival are reduced and the risk of serious
`infections is increased in transplanted diabetics. Although, in the current clinical practice, the
`immunosuppressive therapy is similar between the two groups, data on higher rate of infection
`imply that diabetics may be more immunosuppressed than their non-diabetic counterparts.
`Personalized immunosuppressive therapy, by means of devising appropriate diagnostic methods,
`may therefore reduce the occurrence of unwanted events thereby improving graft and patient
`survival. This project is aimed to estimate specific PK/PD parameters of immunosuppressive
`agents for patients with diabetes type (1 or 2) or with respect to the degree of glucose control. The
`hypothesis is that the effective concentration of some immunosuppressive agent is different
`between diabetic and non-diabetic patients as a function of diabetes type or glucose control. The
`other aim of this project is to evaluate the influence of diabetes type and glucose control on the
`cytochrome P450 3A (CYP3A) activity and metabolism of immunosuppressive agents.
`
`To date, we have observed that diabetes significantly reduced the concentration of some of the
`cyclosporine metabolites (Dostalek et al. 2011), while the exposure to tacrolimus metabolites was
`not affected by diabetes (Chitnis et a1. 2012). A clinical PKPD study is underway aiming to
`elucidate the metabolism of sirolimus in diabetic patients (funded by Pfizer). We have also
`observed altered concentrations of mycophenolic acid glucuronidated metabolites in diabetic
`patients (Akhlaghi et a1. 2006; Patel et al. 2007), which may indicate an effect of diabetes on phase
`II metabolism or transporters. Altered concentrations of prednisolone and cortisol were also
`
`F. Akhlaghi
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`C VJune 2017
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`observed in diabetic patients (Ionita et a1. under review). These observations, have led us to study
`the expression and activity of drug metabolizing enzymes in diabetic livers and kidneys.
`Moreover, diabetes is associated with delayed gastric emptying time and altered GI pH. The effect
`of gastric residence time and GI pH was characterized on the disposition of immunosuppressive
`agents was characterized using an FDA approved system named SmartPillTM technology. The data
`analysis of this study that is funded by Novartis is currently ongoing.
`
`(ii)
`
`To study enzyme activity and protein expression for major phase I and phase II drug
`metabolizing enzymes in diabetic and non-diabetic tissues.
`
`Patients with diabetes mellitus require pharmacotherapy with numerous medications. However,
`the effect of diabetes on drug biotransforrnation is not well understood in human. This study was
`designed to investigate the effect of diabetes on liver cytochrome P450 3As, the most abundant
`phase I drug-metabolizing enzymes that oxidize numerous clinically, physiologically, and
`toxicologically important compounds. Using liver samples from diabetic and non-diabetic donors
`genotyped for CYP3A4*1B and CYP3A5*3 polymorphism, we have compared cytochrome P450
`3A4, 3A5, and 2E1 mRNA expression, protein level, and enzyme activity between diabetic and
`non-diabetic subjects. The results showed pronouncedly lower P450 CYP3A4 activity in diabetic
`livers, whereas P450 3A5 protein level or mRNA expressions were comparable between the two
`groups. Concurrently, we observed increased P450 2E1 protein level and activity, characterized
`by higher chlorzoxazone 6-hydroxylation, in diabetic HLMs. The manuscript from this study
`(Dostalek et al. 2011) was published at the British Journal of Pharmacology. The result of this
`study also provides mechanistic explanation for reduced metabolite concentration of cyclosporine
`(a CYP3A4 substrate) but not tacrolimus that is also metabolized by CYP3A5. This study was
`funded by American Heart Association.
`
`Moreover, MPA biotransforrnation and UDP—glucuronosyltransferases (UGTs) expression and
`activity were compared between liver and kidney from diabetic and non-diabetic donors.
`Glucuronidation of MPA as well as the expression and a probe substrate activity of UGTs primarily
`responsible for MPA phenol glucuronide (MPAG) formation (UGTlAl, 1A9), and MPA acyl
`glucuronide (AcMPAG) formation (UGT2B7). We have found both diabetic and non-diabetic
`human liver microsomes (HLM) and kidney microsomes (HKM) formed MPAG with similar
`efficiency; however, AcMPAG formation was significantly lower in diabetic samples. Supporting
`this finding, markedly lower glucuronidation of the UGT2B7 probe 3’-azido-3’-deoxythymidine,
`UGT2B7 protein and UGT2B7 mRNA was observed in diabetic tissues. UGT genetic
`polymorphism did not explain this difference since UGT2B7*2 or *lc genotype were not
`associated with altered microsomal UGT2B7 protein levels or AcMPAG formation. Furthermore,
`mRNA expression and probe activities for UGTlAl or UGTlA9, both forming MPAG but not
`AcMPAG, were comparable between diabetic and non-diabetic tissues suggesting the effect may
`be specific to UGT2B7 mediated AcMPAG formation. These findings suggest that diabetes
`mellitus is associated with significantly reduced UGT2B7 mRNA expression, protein level, and
`enzymatic activity of human liver and kidney, explaining in part the relatively low circulating
`concentrations of AcMPAG in diabetic patients. This study is published in Drug metabolism and
`Disposition (Dostalek et al. 2011) and was funded by Novartis.
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`F. Akhlaghi
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`CVJune 2017
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`(iii)
`
`To study the disposition of statin lipid lowering agents in type 2 diabetic patients and
`to identify factors (i.e. CYP3A activity, genetic polymorphism, pro-inflammatory
`cytokines) in predisposing a diabetic patient to statin related myopathy.
`
`Adverse drug reactions (ADRs) are the 4th major cause of death in the United States, the cost
`associated with drug-related morbidity, and mortality is estimated to be $136 billion per year. The
`incidence of ADRs is increased exponentially in patients who routinely take 4 for more
`medications. Individuals with diabetes mellitus are an example of such patients, although
`surprisingly, very little is known about the effect of diabetes mellitus on the pharrnacokinetics and
`disposition of commonly used drugs. HMG—CoA reductase inhibitors (statins) are commonly used
`lipid lowering agents; however, up to 7% of patients treated with statins exhibit symptoms of
`muscle toxicity and ~0.5 percent develop potentially fatal rhabdomyolysis (severe muscle
`breakdown). Atorvasatin (ATV, Lipitor®, Pfizer) is the most frequently prescribed statin, yet to
`date, its pharrnacokinetics has never been studied in diabetic patients. Epidemiological evidence
`suggests that the incidence of ATV induced rhabdomyolysis requiring hospitalization is three
`times higher in diabetic patients. Administered as an acid, ATV is converted to a lipophilic and
`more toxic lactone form. We have recently observed plasma concentration of ATV lactone was
`significantly elevated in diabetic patients, which may explain the higher incidence of ATV related
`side effects in diabetics.
`The broad long-term objective of this project
`is to optimize
`pharmacotherapy with statins to the individual need of each diabetic patient. The central
`hypothesis is that down regulation of CPY3A enzymes lead to elevated concentration of ATV-
`lactone. The rationale for this project is to identify patients’ inherent propensity to develop
`myopathy so those patients can be administered statins (such as rosuvastatin) that are not CYP3A
`substrate. We have already developed and validated a very simple LC-MS/MS method for
`determination of ATV acid and five of its metabolites using 50-microL plasma (Macwan 2011,
`Macwan 2012). We have characterized ATV and metabolite concentration in 52 diabetic and non-
`diabetic transplant recipients and observed the concentration of ATV lactone to be 5-10 folds
`higher in diabetic patients.
`In vitro, diabetic livers were not capable of biotransforming ATV
`lactone