Elevated serum creatinine (S ) caused by the inhibition of renal transporter(s) may be misinterpreted as kidney injury. The interpretation is more complicated in chronic kidney disease (CKD) patients due to altered disposition of creatinine and renal transporter inhibitors. A clinical study was conducted in 17 CKD patients (estimated glomerular filtration rate 15-59 mL/min/1.73m ); changes in S were monitored during trimethoprim treatment (100-200 mg/day), administered to prevent recurrent urinary infection, relative to the baseline level. Additional S -interaction data with trimethoprim, cimetidine, and famotidine in CKD patients were collated from the literature. Our published physiologically-based creatinine model was extended to predict the effect of the CKD on S and creatinine-drug interaction. The creatinine-CKD model incorporated age/sex-related differences in creatinine synthesis, CKD-related glomerular filtration deterioration; change in transporter activity either proportional or disproportional to GFR decline were explored. Optimized models successfully recovered baseline S from 64 CKD patients (geometric mean fold-error of 1.1). Combined with pharmacokinetic models of inhibitors, the creatinine model was used to simulate transporter-mediated creatinine-drug interactions. Use of inhibitor unbound plasma concentrations resulted in 66% of simulated S interaction data within the prediction limits, with cimetidine interaction significantly under-estimated. Assuming that transporter activity deteriorates disproportional to GFR decline resulted in higher predicted sensitivity to transporter inhibition in CKD patients relative to healthy, consistent with sparse clinical data. For the first time, this novel modelling approach enables quantitative prediction of S in CKD and delineation of the effect of disease and renal transporter inhibition in this patient population.
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