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Abstract: PO2023

Tenofovir Kidney Clearance Predicted by Glomerular and Tubular Secretory Functions

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Granda, Michael L., University of Washington, Seattle, Washington, United States
  • Yeung, Catherine K., University of Washington, Seattle, Washington, United States
  • Prince, David K., University of Washington, Seattle, Washington, United States
  • Hoofnagle, Andrew N., University of Washington, Seattle, Washington, United States
  • Kestenbaum, Bryan R., University of Washington, Seattle, Washington, United States

Group or Team Name

  • Kestenbaum
Background

Proximal tubular secretion is the primary kidney mechanism for eliminating most prescribed medications. Yet, kidney drug dosing is based on estimates of the glomerular filtration rate (GFR). In an empiric pharmacokinetic study, we compared GFR and secreted endogenous solute clearances for predicting the kidney elimination of tenofovir disoproxil fumarate (TDF), a drug with complex kidney handling.

Methods

We recruited 27 adult patients across a wide range of kidney function. Exclusion criteria were use of tenofovir or a secretory antagonist (cimetidine, digoxin, probenecid), dialysis, nephrotic syndrome, or cirrhosis. We administered a single 125mg oral dose of TDF and estimated its kidney clearance from the area under the plasma time concentration curve and urine drug recovery. We measured GFR by iohexol clearance (iGFR) and estimated secretory function from a 10-hour urine collection with mass-spectroscopy measurements of endogenous secretory solutes. We used linear regression, leave one out cross-validation, root mean squared error, and mean percentage error to describe agreement between kidney functions and TDF clearance.

Results

Mean age of the study population was 55 +15 years, 63% were male, and median iGFR was 78 ml/min/1.73m2 (IQR 52, 99 ml/min/1.73m2); ten participants (37%) had an iGFR <60 ml/min/1.73m2. The mean percentage error (MPE) between observed and iGFR-predicted TDF kidney clearance was 26.7% (Table). The clearances of four endogenous secretory solutes improved the prediction of TDF clearance beyond that of iGFR: cinnamoylglycine, indoxyl sulfate, isovalerylglycine, and tiglylglycine. Combining solute clearance and iGFR results in a lower overall mean percentage error in TDF kidney clearance prediction.

Conclusion

Measurements of secretory solute clearance represent a potential future strategy for improving kidney drug dosing.

Funding

  • NIDDK Support