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OPTIMIZATION OF MYCOPHENOLATE MOFETIL DOSING IN TRANSPLANT PATIENTS

Joshi, Rujuta (2018) OPTIMIZATION OF MYCOPHENOLATE MOFETIL DOSING IN TRANSPLANT PATIENTS. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Mycophenolate Mofetil (MMF) is an immunosuppressive pro-drug of mycophenolic acid (MPA), first approved by the US Food and Drug Administration (FDA) in 1995 for the prevention of rejection post solid organ transplantation (SOT). A narrow therapeutic index, poor predictability of exposure from trough drug level monitoring, large inter transplant as well as inter and intra subject variability and lack of guidelines for optimal dosing are the primary reasons that make it very crucial to apply pharmacokinetic (PK) and pharmacodynamic (PD) concepts to individualize the dosing of MPA in transplant sub-populations. A target range of the active form, MPA measured by the area under the concentration time curve (AUC) in renal transplant recipients of 30-60 mg*h/L has been shown to be associated with better graft and overall survival. This work attempts at optimizing dosing of MMF in pediatric HSCT recipients and in adult lung transplant recipients by using different dosing regimens, therapeutic drug monitoring and modeling approaches. We evaluated the safety and feasibility of a personalized pharmacokinetics-based dosing approach in pediatric HSCT patients using a novel continuous infusion (CI) method of administration of MMF to improve MPA exposure.
We further evaluated the feasibility of a PK and PD focused dosing of MMF in adult lung transplant (LT) recipients. Total plasma concentrations of MPA measured by a UPLC-MS assay were inversely related to the inosine-5′-monophosphate dehydrogenase (IMPDH) activity, with the lowest activity being seen at the maximum MPA concentration. In a pilot study conducted in LT recipients, although statistically not significant, the pre-dose IMPDH activity at the bronchoscopy visit tended to be higher in patients who rejected compared to those who did not have any rejection episodes. Finally, a robust physiologically based pharmacokinetic (PBPK) model of MPA was built and validated in healthy Caucasian and Chinese volunteers, pediatric patients, kidney transplant recipients and patients with varying degree of renal impairment with an intent to apply this in clinical practice to lung and pediatric HSCT patients. The promising results from this work can serve as the foundation for future studies optimizing the use of MPA in transplant patients.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Joshi, Rujutaruj4@pitt.eduruj40000-0003-1722-2315
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
Committee ChairVenkataramanan, Ramanrv@pitt.edurvUNSPECIFIED
Committee MemberGoyal, Rakeshrakeshkgyl@gmail.comUNSPECIFIEDUNSPECIFIED
Committee MemberPoloyac, Samuelpoloyac@pitt.edupoloyacUNSPECIFIED
Committee MemberHowrie Schiff, Denisehowrie@pitt.eduhowrieUNSPECIFIED
Committee MemberEnsor, Christopherchris.ensor@pitt.educhris.ensorUNSPECIFIED
UNSPECIFIEDBeumer, Janjhb11@pitt.edujhb11UNSPECIFIED
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairVenkataramanan, Ramanrv@pitt.edurv
Committee MemberGoyal, Rakeshrakeshkgyl@gmail.com
Committee MemberPoloyac, Samuelpoloyac@pitt.edupoloyac
Committee MemberBeumer, Janjhb11@pitt.edujhb11
Committee MemberHowrie Schiff, Denisehowrie@pitt.eduhowrie
Ensor, Christopherchris.ensor@pitt.educhris.ensor
Date: 16 March 2018
Date Type: Completion
Defense Date: 16 March 2018
Approval Date: 23 April 2018
Submission Date: 16 April 2018
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 270
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: pediatrics, mycophenolate Mofetil, lung transplant, continuous infusion, stem cell transplant, optimization
Date Deposited: 23 Apr 2018 14:15
Last Modified: 23 Apr 2018 14:15
URI: http://d-scholarship.pitt.edu/id/eprint/34304

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