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Individualized Physiologically Based Pharmacokinetic Modeling of Rate Data (iPBPK-R): A Novel Approach to Estimate the Effect of Kidney Disease on Nonrenal Elimination Pathways

Franchetti, Yoko (2020) Individualized Physiologically Based Pharmacokinetic Modeling of Rate Data (iPBPK-R): A Novel Approach to Estimate the Effect of Kidney Disease on Nonrenal Elimination Pathways. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The impact of chronic kidney disease (CKD) on drug disposition is essential to optimize drug dosing in CKD. Clarifying the role of drug transporters and metabolic enzymes for nonrenally cleared drugs has been an emerging clinical interest for dose optimization. Physiologically-based pharmacokinetic (PBPK) modeling can provide valuable insight in this research area. The primary aim of this dissertation was to develop a novel PBPK approach and measurement procedure, called individualized PBPK modeling of rate data (iPBPK-R) to simultaneously estimate parameters for nonrenal elimination pathways in individuals and evaluate the effect of CKD on these pathways. We first described iPBPK-R which is a signal processing based indirect measurement method for measuring enzyme and transporter activities for individuals. In two subsequent studies, iPBPK-R was applied to 14CO2 production rate data of erythromycin breath test (EBT) in healthy subjects and patients with end-stage renal disease (ESRD) receiving hemodialysis, respectively. Rate data for 14CO2 production, as the approximate first derivative of 14CO2 concentration data, allows iPBPK-R to successfully estimate parameters for nonrenal elimination pathways using the single phenotypic probe 14C-erythromycin regardless of rate-limiting steps. iPBPK-R analysis indicated that CYP3A4 activity is much lower than the baseline IVIVE input in healthy subjects, and females had a higher CYP3A4 activity than males. In ESRD patients, estimated adjustment factors indicated that hemodialysis increased CYP3A4 activity minimally while OATPs activity varied among patients without improvement across hemodialysis. BUN was not correlated with any of the nonrenal elimination pathways suggesting that BUN is not a good candidate biomarker. Lastly, iPBPK-R was extended to its application to multiple concentration datasets of temsirolimus and its metabolite sirolimus in healthy subjects. Both temsirolimus and sirolimus are substrates of CYP3A4 and P-gp, and the effect of concomitantly administered rifampin on these elimination pathways was evaluated. The findings showed that rifampin did not affect CYP3A4 activity on temsirolimus but increased it for sirolimus by 73%. Rifampin did not affect P-gp activity. Collectively, iPBPK-R may facilitate drug dosing based on personalized parameter estimates of nonrenal elimination pathways. iPBPK-R may enable uremic toxin-based biomarker research towards precision dosing in CKD as sketched with hierarchical cluster analysis.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Franchetti, Yokoyof8@pitt.eduyof80000-0001-5587-9962
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairNolin, Thomasnolin@pitt.edunolin
Committee MemberVenkataramanan, Ramanrv@pitt.edurv
Committee MemberBeumer, Janbeumerjh@upmc.edujhb11
Committee MemberEmpey, Philippempey@pitt.edupempey
Committee MemberJhamb,
Date: 3 December 2020
Date Type: Publication
Defense Date: 21 August 2020
Approval Date: 3 December 2020
Submission Date: 17 November 2020
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 308
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: PBPK, CYP3A4, drug transporters, kidney disease, hemodialysis, uremic toxins, physiologically based pharmacokinetics, erythromycin, temsirolimus, sirolimus, indirect measurement, non-linear parameter estimation, breath test, precision medicine
Date Deposited: 03 Dec 2020 14:47
Last Modified: 03 Dec 2020 14:47


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