Effect of Chronic Kidney Disease on the Renal Secretion via Organic Anion Transporters 1/3: Implications for Physiologically-Based Pharmacokinetic Modeling and Dose Adjustment

There is growing evidence that active tubular secretory clearance (CLs) may not decline proportionally with the glomerular filtration rate (GFR) in chronic kidney disease (CKD), leading to the overestimation of renal clearance (CLr) 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 CLr, tubular secretion and protein binding (f(u,p)). The f(u,p) of the collated substrates ranged from 0.0026 to 1.0 in healthy populations; observed CKD-related increase in the f(u,p) (up to 2.7-fold) of 8 highly bound substrates (f(u,p) <= 0.2) was accounted for in the analysis. Use of prediction equation based on disease-related changes in albumin resulted in underprediction of the CKD-related increase in f(u,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 CLr.