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Incorporating Uremic Solute-mediated Inhibition of OAT1/3 Improves PBPK Prediction of Tenofovir Renal and Systemic Disposition in Patients with Severe Kidney Disease

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Abstract

Background

Dose modification of renally secreted drugs in patients with chronic kidney disease (CKD) has relied on serum creatinine concentration as a biomarker to estimate glomerular filtration (GFR) under the assumption that filtration and secretion decline in parallel. A discrepancy between actual renal clearance and predicted renal clearance based on GFR alone is observed in severe CKD patients with tenofovir, a compound secreted by renal OAT1/3. Uremic solutes that inhibit OAT1/3 may play a role in this divergence.

Methods

To examine the impact of transporter inhibition by uremic solutes on tenofovir renal clearance, we determined the inhibitory potential of uremic solutes hippuric acid, indoxyl sulfate, and p-cresol sulfate. The inhibition parameters (IC50) were incorporated into a previously validated mechanistic kidney model; simulated renal clearance and plasma PK profile were compared to data from clinical studies.

Results

Without the incorporation of uremic solute inhibition, the PBPK model failed to capture the observed data with an absolute average fold error (AAFE) > 2. However, when the inhibition of renal uptake transporters and uptake transporters in the slow distribution tissues were included, the AAFE value was within the pre-defined twofold model acceptance criterion, demonstrating successful model extrapolation to CKD patients.

Conclusion

A PBPK model that incorporates inhibition by uremic solutes has potential to better predict renal clearance and systemic disposition of secreted drugs in patients with CKD. Ongoing research is warranted to determine if the model can be expanded to include other OAT1/3 substrate drugs and to evaluate how these findings can be translated to clinical guidance for drug selection and dose optimization in patients with CKD.

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Data Availability

The datasets and models generated during the current study have not been deposited into a publicly available database but are available from the corresponding author on reasonable request.

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Acknowledgements

CKY would like to gratefully acknowledge Dr. David E. Smith for his steady guidance, unwavering support, and good humor.

Funding

These studies were supported by funding from the National Institutes of Health National Institute of General Medical Sciences (NIGMS) R01GM121354, National Institute on Drug Abuse (NIDA) P01DA032507, and an unrestricted gift from the Northwest Kidney Centers to the Kidney Research Institute. A.C. and W.H. were recipients of the Warren G. Magnuson Scholarship at the University of Washington.

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Author notes

  1. Shih-Yu Chang

    Present address: Janssen Research and Development, Raritan, NJ, USA

  2. Weize Huang

    Present address: Genentech Inc, South San Francisco, CA, USA

  3. Antonio J. López Quiñones

    Present address: Revolution Medicines, San Francisco, CA, USA

Authors and Affiliations

  1. Department of Pharmacy, School of Pharmacy, University of Washington, 1959 NE Pacific St. H375, Box 357630, Seattle, WA, 98195, USA

    Shih-Yu Chang & Catherine K. Yeung

  2. Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, 98195, USA

    Weize Huang, Alenka Chapron, Antonio J. López Quiñones, Joanne Wang, Nina Isoherranen, Danny D. Shen & Edward J. Kelly

  3. Division of Nephrology, Department of Medicine, Kidney Research Institute, University of Washington, Seattle, WA, 98195, USA

    Edward J. Kelly, Jonathan Himmelfarb & Catherine K. Yeung

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Contributions

SYC, AC, AL, JW, NI, DS, EK, JH, and CKY developed and designed the experiments, SYC, AC, and AL conducted the experiments and data analysis. WH and NI developed the PBPK model and performed simulations. All authors contributed to writing and editing the manuscript.

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Correspondence to Catherine K. Yeung.

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Shih-Yu Chang and Weize Huang are co-first authors that contributed equally to the manuscript.

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Chang, SY., Huang, W., Chapron, A. et al. Incorporating Uremic Solute-mediated Inhibition of OAT1/3 Improves PBPK Prediction of Tenofovir Renal and Systemic Disposition in Patients with Severe Kidney Disease. Pharm Res 40, 2597–2606 (2023). https://doi.org/10.1007/s11095-023-03594-x

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