Predicting complex kidney drug handling using a physiologically-based pharmacokinetic model informed by biomarker-estimated secretory clearance and blood flow
© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics..
Kidney function-adjusted drug dosing is currently based solely on the estimated glomerular filtration rate (GFR), however, kidney drug handling is accomplished by a combination of filtration, tubular secretion, and re-absorption. Mechanistic physiologically-based pharmacokinetic (PBPK) models recapitulate anatomic compartments to predict elimination from estimated perfusion, filtration, secretion, and re-absorption, but clinical applications are limited by a lack of empiric individual-level measurements of these functions. We adapted and validated a PBPK model to predict drug clearance from individual biomarker-based estimates of kidney perfusion and secretory clearance. We estimated organic anion transporter-mediated secretion via kynurenic acid clearance and kidney blood flow (KBF) via isovalerylglycine clearance in human participants, incorporating these measurements with GFR into the model to predict kidney drug clearance. We compared measured and model-predicted clearances of administered tenofovir and oseltamivir, which are cleared by both filtration and secretion. There were 27 outpatients (age 55 ± 15 years, mean iohexol-GFR [iGFR] 76 ± 31 mL/min/1.73 m2 ) in this drug clearance study. The mean observed and mechanistic model-predicted tenofovir clearances were 169 ± 102 mL/min and 163 ± 80 mL/min, respectively; estimated mean error of the mechanistic model was 37.1 mL/min (95% confidence interval [CI]: 24-52.9), compared to a mean error of 41.8 mL/min (95% CI: 25-61.6) from regression model. The mean observed and model-predicted oseltamivir carboxylate clearances were 183 ± 104 mL/min and 179 ± 89 mL/min, respectively; estimated mean error of the mechanistic model was 42.9 mL/min (95% CI: 29.7-56.4), versus error of 48.1 mL/min (95% CI: 31.2-67.3) from the regression model. Individualized estimates of tubular secretion and KBF improved the accuracy of PBPK model-predicted tenofovir and oseltamivir kidney clearances, suggesting the potential for biomarker-informed measures of kidney function to refine personalized drug dosing.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:17 |
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| Enthalten in: |
Clinical and translational science - 17(2024), 1 vom: 01. Jan., Seite e13678 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Granda, Michael L [VerfasserIn] |
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| Links: |
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| Themen: |
20O93L6F9H |
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| Anmerkungen: |
Date Completed 25.01.2024 Date Revised 17.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/cts.13678 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM364131284 |
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| 520 | |a © 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. | ||
| 520 | |a Kidney function-adjusted drug dosing is currently based solely on the estimated glomerular filtration rate (GFR), however, kidney drug handling is accomplished by a combination of filtration, tubular secretion, and re-absorption. Mechanistic physiologically-based pharmacokinetic (PBPK) models recapitulate anatomic compartments to predict elimination from estimated perfusion, filtration, secretion, and re-absorption, but clinical applications are limited by a lack of empiric individual-level measurements of these functions. We adapted and validated a PBPK model to predict drug clearance from individual biomarker-based estimates of kidney perfusion and secretory clearance. We estimated organic anion transporter-mediated secretion via kynurenic acid clearance and kidney blood flow (KBF) via isovalerylglycine clearance in human participants, incorporating these measurements with GFR into the model to predict kidney drug clearance. We compared measured and model-predicted clearances of administered tenofovir and oseltamivir, which are cleared by both filtration and secretion. There were 27 outpatients (age 55 ± 15 years, mean iohexol-GFR [iGFR] 76 ± 31 mL/min/1.73 m2 ) in this drug clearance study. The mean observed and mechanistic model-predicted tenofovir clearances were 169 ± 102 mL/min and 163 ± 80 mL/min, respectively; estimated mean error of the mechanistic model was 37.1 mL/min (95% confidence interval [CI]: 24-52.9), compared to a mean error of 41.8 mL/min (95% CI: 25-61.6) from regression model. The mean observed and model-predicted oseltamivir carboxylate clearances were 183 ± 104 mL/min and 179 ± 89 mL/min, respectively; estimated mean error of the mechanistic model was 42.9 mL/min (95% CI: 29.7-56.4), versus error of 48.1 mL/min (95% CI: 31.2-67.3) from the regression model. Individualized estimates of tubular secretion and KBF improved the accuracy of PBPK model-predicted tenofovir and oseltamivir kidney clearances, suggesting the potential for biomarker-informed measures of kidney function to refine personalized drug dosing | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Oseltamivir |2 NLM | |
| 650 | 7 | |a 20O93L6F9H |2 NLM | |
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| 650 | 7 | |a Tenofovir |2 NLM | |
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| 700 | 1 | |a Huang, Weize |e verfasserin |4 aut | |
| 700 | 1 | |a Yeung, Catherine K |e verfasserin |4 aut | |
| 700 | 1 | |a Isoherranen, Nina |e verfasserin |4 aut | |
| 700 | 1 | |a Kestenbaum, Bryan |e verfasserin |4 aut | |
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