Abstract: PO2360
Prediction of Kidney Drug Clearance: A Comparison of Tubular Secretory Clearance and GFR
Session Information
- Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
Authors
- Chen, Yan, University of Washington Department of Epidemiology, Seattle, Washington, United States
- Zelnick, Leila R., Kidney Research Institute, Seattle, Washington, United States
- Hoofnagle, Andrew N., Kidney Research Institute, Seattle, Washington, United States
- Yeung, Catherine K., University of Washington Department of Pharmacy, Seattle, Washington, United States
- Shireman, Laura M., University of Washington Department of Pharmacy, Seattle, Washington, United States
- Brauchla, Calder C., University of Washington Department of Pharmacy, Seattle, Washington, United States
- de Boer, Ian H., Kidney Research Institute, Seattle, Washington, United States
- Himmelfarb, Jonathan, Kidney Research Institute, Seattle, Washington, United States
- Kestenbaum, Bryan R., Kidney Research Institute, Seattle, Washington, United States
Background
Tubular secretion is the primary mechanism of kidney drug elimination. Few studies have empirically evaluated the role of tubular secretion on the kidney elimination of administered drugs.
Methods
We evaluated 54 participants with and without chronic kidney disease. We administered a single dose of iohexol, furosemide, and famciclovir at the start of the study visit. We used LC-MS/MS to measure furosemide, penciclovir (the active form of famciclovir), and secretory solutes in sequential timed plasma samples and timed urine collections. We compared iohexol GFR (iGFR) with the kidney clearances of secretory solutes for predicting kidney drug clearance using mean absolute errors (MAE) derived from linear regression and leave-one-out cross-validation.
Results
Participants were characterized by a mean age of 55 years and a median iGFR of 73 ml/min/1.73m2. Using iGFR as a single predictor, the MAE between model-predicted and measured furosemide and penciclovir clearance was 40.1 and 64.1 ml/min, respectively. The MAEs for models of individual secretory solute clearances were statistically similar to that of the iGFR model. The addition of kynurenic acid, pyridoxic acid, isovalerylglycine, and tiglylglycine clearances each individually improved the predictive accuracy of penciclovir clearance compared with the iGFR model.
Conclusion
The kidney clearance of secretory solutes and iGFR showed similar accuracy for predicting the clearances of furosemide and penciclovir, with some improvement from combining both measures. These findings provide cautious optimism that measurements of secretory clearance may improve kidney drug dosing.
Accuracy of GFR and secretory solute clearances for predicting kidney clearance of furosemide and penciclovir
| Furosemide | Penciclovir | |||||||
| Secretory clearance as a single predictor | Secretory clearance plus iGFR as predictors | Secretory clearance as a single predictor | Secretory clearance plus iGFR as predictors | |||||
| MAE between predicted and measured drug clearance, ml/min | Difference in MAE comparing iGFR to secretory clearance, ml/min (95% CI)a | MAE between predicted and measured drug clearance, ml/min | Difference in MAE comparing iGFR alone to iGFR plus individual secretory clearance, ml/min (95% CI)a | MAE between predicted and measured drug clearance, ml/min | Difference in MAE comparing iGFR to secretory clearance, ml/min (95% CI)a | MAE between predicted and measured drug clearance, ml/min | Difference in MAE comparing iGFR alone to iGFR plus individual secretory clearance, ml/min (95% CI)a | |
| Pyridoxic acid | 37.7 | 2.4 (-6.1, 9.7) | 35.4 | 4.7 (-0.4, 10.5) | 62.4 | 1.7 (-12.9, 16.2) | 56.3 | 7.8 (0.9, 16.2) |
| Isovalerylglycine | 40.6 | -0.5 (-14.2, 10.8) | 36.9 | 3.2 (-1.7, 14.1) | 60.3 | 3.8 (-13.9, 21.7) | 50.8 | 13.3 (2.3, 27.4) |
| Tiglyglycine | 38.9 | 1.2 (-14.1, 12.8) | 34.2 | 5.9 (-1.3, 16.3) | 69.8 | -5.7 (-22.3, 12.8) | 54.8 | 9.3 (0.9, 19.0) |
| Kynurenic acid | 37.4 | 2.7 (-8.7, 12.0) | 33.3 | 6.8 (-0.4, 13.5) | 70.7 | -6.6 (-22.0, 14.6) | 54.8 | 9.3 (0.1, 21.1) |
| Cinnamoylglycine | 36.6 | 3.5 (-5.3, 11.2) | 34.9 | 5.2 (-1.9, 11.8) | 70.9 | -6.8 (-23.1, 9.2) | 61.3 | 2.8 (-2.3, 11.4) |
| Indoxyl sulfate | 39.6 | 0.5 (-7.6, 9.1) | 35.6 | 4.5 (-0.3, 10.6) | 76.0 | -11.9 (-25.3, 2.4) | 61.7 | 2.4 (-1.5, 8.7) |
| p-cresol sulfate | 38.9 | 1.2 (-6.6, 8.2) | 37.2 | 2.9 (-0.6, 8.7) | 61.9 | 2.2 (-12.1, 14.7) | 57.6 | 6.5 (-0.4, 15.5) |
| Summary secretion score | 31.0 | 9.1 (-1.7, 17.0) | 31.6 | 8.5 (-0.2, 16.3) | 53.2 | 10.9 (-2.9, 24.8) | 52.3 | 11.8 (3.8, 24.0) |
a Positive values indicate greater agreement for secretory clearances.
Funding
- NIDDK Support