TY - JOUR
T1 - Effect of chronic kidney disease on the renal secretion via organic anion transporters (OAT)1/3: Implications for PBPK modelling and dose adjustment
AU - Tan, Shawn Pei Feng
AU - Scotcher, Daniel
AU - Rostami‐hodjegan, Amin
AU - Galetin, Aleksandra
PY - 2022/5/15
Y1 - 2022/5/15
N2 - There is growing evidence that active tubular secretory clearance (CLs) may not decline proportionally with glomerular filtration rate (GFR) in chronic kidney disease (CKD), leading to the overestimation of renal clearance when using solely GFR to approximate disease effect on renal elimination. The clinical pharmacokinetic data of 33 renally secreted OAT1/3 substrates were collated to investigate the impact of mild, moderate and severe CKD on renal clearance, tubular secretion and protein binding (fu,p). The fu,p of the collated substrates ranged from 0.0026 to 1.0 in healthy populations; observed CKD-related increase in the fu,p (up to 2.7-fold) of eight highly bound substrates (fu,p ≤ 0.2) was accounted for in the analysis. Use of prediction equation based on disease-related changes in albumin resulted in under-prediction of the CKD-related increase in fu,p of highly bound substrates, highlighting the necessity to measure protein binding in severe CKD. The critical analysis of clinical data for 33 OAT1/3 probes established that decrease in OAT1/3 activity proportional to the changes in GFR was insufficient to recapitulate effects of severe CKD on unbound tubular secretion clearance. OAT1/3-mediated CLs was estimated to decline by an additional 50% relative to the GFR decline in severe CKD, whereas change in active secretion in mild and moderate CKD was proportional to GFR. Consideration of this additional 50% decline in OAT1/3-mediated CLs is recommended for physiologically-based pharmacokinetic models and dose adjustment of OAT1/3 substrates in severe CKD, especially for substrates with high contribution of the active secretion to renal clearance.
AB - There is growing evidence that active tubular secretory clearance (CLs) may not decline proportionally with glomerular filtration rate (GFR) in chronic kidney disease (CKD), leading to the overestimation of renal clearance when using solely GFR to approximate disease effect on renal elimination. The clinical pharmacokinetic data of 33 renally secreted OAT1/3 substrates were collated to investigate the impact of mild, moderate and severe CKD on renal clearance, tubular secretion and protein binding (fu,p). The fu,p of the collated substrates ranged from 0.0026 to 1.0 in healthy populations; observed CKD-related increase in the fu,p (up to 2.7-fold) of eight highly bound substrates (fu,p ≤ 0.2) was accounted for in the analysis. Use of prediction equation based on disease-related changes in albumin resulted in under-prediction of the CKD-related increase in fu,p of highly bound substrates, highlighting the necessity to measure protein binding in severe CKD. The critical analysis of clinical data for 33 OAT1/3 probes established that decrease in OAT1/3 activity proportional to the changes in GFR was insufficient to recapitulate effects of severe CKD on unbound tubular secretion clearance. OAT1/3-mediated CLs was estimated to decline by an additional 50% relative to the GFR decline in severe CKD, whereas change in active secretion in mild and moderate CKD was proportional to GFR. Consideration of this additional 50% decline in OAT1/3-mediated CLs is recommended for physiologically-based pharmacokinetic models and dose adjustment of OAT1/3 substrates in severe CKD, especially for substrates with high contribution of the active secretion to renal clearance.
U2 - 10.1002/cpt.2642
DO - 10.1002/cpt.2642
M3 - Article
SN - 0009-9236
JO - Clinical Pharmacology & Therapeutics
JF - Clinical Pharmacology & Therapeutics
ER -