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Determining the Effects of Chronic Kidney Disease on Organic Anion Transporter1/3 Activity Through Physiologically Based Pharmacokinetic Modeling

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Abstract

Background and Objective

The renal excretion of drugs via organic anion transporters 1 and 3 (OAT1/3) is significantly decreased in patients with renal impairment. This study uses physiologically based pharmacokinetic models to quantify the reduction in OAT1/3-mediated secretion of drugs throughout varying stages of chronic kidney disease.

Methods

Physiologically based pharmacokinetic models were constructed for four OAT1/3 substrates in healthy individuals: acyclovir, meropenem, furosemide, and ciprofloxacin. Observed data from drug–drug interaction studies with probenecid, a potent OAT1/3 inhibitor, were used to parameterize the contribution of OAT1/3 to the renal elimination of each drug. The models were then translated to patients with chronic kidney disease by accounting for changes in glomerular filtration rate, kidney volume, renal blood flow, plasma protein binding, and hematocrit. Additionally, a relationship was derived between the estimated glomerular filtration rate and the reduction in OAT1/3-mediated secretion of drugs based on the renal extraction ratios of ƿ-aminohippuric acid in patients with varying degrees of renal impairment. The relationship was evaluated in silico by evaluating the predictive performance of each final model in describing the pharmacokinetics (PK) of drugs across stages of chronic kidney disease.

Results

OAT1/3-mediated renal excretion of drugs was found to be decreased by 27–49%, 50–68%, and 70–96% in stage 3, stage 4, and stage 5 of chronic kidney disease, respectively. In support of the parameterization, physiologically based pharmacokinetic models of four OAT1/3 substrates were able to adequately characterize the PK in patients with different degrees of renal impairment. Total exposure after intravenous administration was predicted within a 1.5-fold error and 85% of the observed data points fell within a 1.5-fold prediction error. The models modestly under-predicted plasma concentrations in patients with end-stage renal disease undergoing intermittent hemodialysis. However, results should be interpreted with caution because of the limited number of molecules analyzed and the sparse sampling in observed chronic kidney disease pharmacokinetic studies.

Conclusions

A quantitative understanding of the reduction in OAT1/3-mediated excretion of drugs in differing stages of renal impairment will contribute to better predictive accuracy for physiologically based pharmacokinetic models in drug development, assisting with clinical trial planning and potentially sparing this population from unnecessary toxic exposures.

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Authors and Affiliations

  1. School of Pharmacy, University of Waterloo, Waterloo, ON, Canada

    Samuel Dubinsky, Paul Malik, Dagmar M. Hajducek & Andrea Edginton

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  1. Samuel Dubinsky
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  2. Paul Malik
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  3. Dagmar M. Hajducek
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  4. Andrea Edginton
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Correspondence to Andrea Edginton.

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SD, PM, and AE conceptualized the idea and topic of this article. SD and PM contributed to a healthy adult PBPK model construction of the investigative drugs analyzed within this article. SD conducted the CKD-PBPK simulations and analyzed the results. DH was instrumental in the development and finalization of the OAT parameterization function used throughout the CKD-PBPK simulations. Contributions from PM were final as of 11 June, 2021. Preparation of the final manuscript was conducted by SD. The final version of manuscript was reviewed by all authors.

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Dubinsky, S., Malik, P., Hajducek, D.M. et al. Determining the Effects of Chronic Kidney Disease on Organic Anion Transporter1/3 Activity Through Physiologically Based Pharmacokinetic Modeling. Clin Pharmacokinet 61, 997–1012 (2022). https://doi.org/10.1007/s40262-022-01121-6

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  • DOI: https://doi.org/10.1007/s40262-022-01121-6

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