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Characterization of Renal Anionic Drug Transport Capacity in Kidney Transplant Recipients with Persistent BK Viremia: Pharmacokinetic and Pharmacodynamic Studies of Cidofovir

Momper, Jeremiah (2011) Characterization of Renal Anionic Drug Transport Capacity in Kidney Transplant Recipients with Persistent BK Viremia: Pharmacokinetic and Pharmacodynamic Studies of Cidofovir. Doctoral Dissertation, University of Pittsburgh.

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    Abstract

    Kidney transplantation is the treatment of choice for end-stage renal disease (ESRD), and drug therapy plays a significant role in the management of transplant recipients. A variety of commonly used drugs are actively secreted by transporters in the kidney, yet the functional expression and activity of these proteins in transplant patients has not been investigated. The first objective of this research was to characterize anionic tubular secretion capacity in kidney transplant recipients by evaluating the pharmacokinetics of cidofovir, a prototypical organic anion transporter substrate frequently used to treat BK virus infections in this patient population. A sensitive and specific analytical technique was developed to measure cidofovir concentrations in human plasma. Pharmacokinetic analysis of cidofovir in adult kidney transplant recipients suggested reduced OAT1-mediated secretion in these patients. The mechanistic basis of this observation was evaluated in a syngeneic rat model of kidney transplantation, which established that the transplant process itself leads to a sustained reduction in the expression of anionic transport proteins localized to the basolateral membrane of the renal proximal tubule. Additionally, apical anionic transporters were differentially regulated in this model. The next objective was to evaluate the pharmacodynamics of cidofovir in kidney transplant patients. This study demonstrated that cidofovir transiently reduced the degree of BK viremia and viruria in vivo, though the effect was not sustained, and viral loads returned to baseline by the next sampling period. A retrospective analysis employed serum creatinine-based estimates of cidofovir clearance in a large cohort of kidney transplant recipients to approximate aggregate cidofovir exposure, and correlated drug exposure with virologic response. Higher systemic exposure was significantly associated with a larger reduction in the degree of BK viremia. However, only 11% of the variance in the decline in the BK viral load could be explained by variation in cumulative cidofovir exposure, indicating that other factors, likely immune-mediated, play a major role in viral clearance. Collectively, this work broadens our understanding of drug disposition in kidney transplant recipients and provides fundamental knowledge that may improve the treatment of BK virus infections.


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    Item Type: University of Pittsburgh ETD
    Creators/Authors:
    CreatorsEmailORCID
    Momper, Jeremiahjdm14@pitt.edu
    ETD Committee:
    ETD Committee TypeCommittee MemberEmailORCID
    Committee ChairVenkataramanan, Ramanrv@pitt.edu
    Committee MemberNolin, Thomasnolin@pitt.edu
    Committee MemberSchonder, Kristineschonderks@upmc.edu
    Committee MemberShapiro, Ronshapiror@upmc.edu
    Committee MemberXie, Wenwex6@pitt.edu
    Committee MemberZemaitis, Michaelmaz@pitt.edu
    Title: Characterization of Renal Anionic Drug Transport Capacity in Kidney Transplant Recipients with Persistent BK Viremia: Pharmacokinetic and Pharmacodynamic Studies of Cidofovir
    Status: Published
    Abstract: Kidney transplantation is the treatment of choice for end-stage renal disease (ESRD), and drug therapy plays a significant role in the management of transplant recipients. A variety of commonly used drugs are actively secreted by transporters in the kidney, yet the functional expression and activity of these proteins in transplant patients has not been investigated. The first objective of this research was to characterize anionic tubular secretion capacity in kidney transplant recipients by evaluating the pharmacokinetics of cidofovir, a prototypical organic anion transporter substrate frequently used to treat BK virus infections in this patient population. A sensitive and specific analytical technique was developed to measure cidofovir concentrations in human plasma. Pharmacokinetic analysis of cidofovir in adult kidney transplant recipients suggested reduced OAT1-mediated secretion in these patients. The mechanistic basis of this observation was evaluated in a syngeneic rat model of kidney transplantation, which established that the transplant process itself leads to a sustained reduction in the expression of anionic transport proteins localized to the basolateral membrane of the renal proximal tubule. Additionally, apical anionic transporters were differentially regulated in this model. The next objective was to evaluate the pharmacodynamics of cidofovir in kidney transplant patients. This study demonstrated that cidofovir transiently reduced the degree of BK viremia and viruria in vivo, though the effect was not sustained, and viral loads returned to baseline by the next sampling period. A retrospective analysis employed serum creatinine-based estimates of cidofovir clearance in a large cohort of kidney transplant recipients to approximate aggregate cidofovir exposure, and correlated drug exposure with virologic response. Higher systemic exposure was significantly associated with a larger reduction in the degree of BK viremia. However, only 11% of the variance in the decline in the BK viral load could be explained by variation in cumulative cidofovir exposure, indicating that other factors, likely immune-mediated, play a major role in viral clearance. Collectively, this work broadens our understanding of drug disposition in kidney transplant recipients and provides fundamental knowledge that may improve the treatment of BK virus infections.
    Date: 05 December 2011
    Date Type: Publication
    Defense Date: 29 September 2011
    Approval Date: 05 December 2011
    Submission Date: 21 November 2011
    Release Date: 05 December 2011
    Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
    Patent pending: No
    Number of Pages: 242
    Institution: University of Pittsburgh
    Thesis Type: Doctoral Dissertation
    Refereed: Yes
    Degree: PhD - Doctor of Philosophy
    Uncontrolled Keywords: Pharmacokinetics; Pharmacodynamics; Cidofovir; BK Virus; Transplantation; Drug Transporters
    Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
    Date Deposited: 05 Dec 2011 15:26
    Last Modified: 16 Jul 2014 17:03

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