Abstract
There is growing evidence that active tubular secretory clearance (CL(s) ) may not decline proportionally with the glomerular filtration rate (GFR) in chronic kidney disease (CKD), leading to the overestimation of renal clearance (CL(r) ) 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 CL(r) , 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 CL(s) 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 CL(s) 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 CL(r) .