A Joint Pharmacometric Model of Iohexol and Creatinine Administered through a Meat Meal to Assess GFR and Renal OCT2/MATE Activity

Abstract

Accurately assessing glomerular filtration rate (GFR) from plasma creatinine concentrations is challenging in patients with unstable renal function. This study aimed to refine the understanding of creatinine kinetics for more reliable assessments of GFR and net creatinine tubular secretion (nCTS) via OCT2/MATE in humans. In a clinical study of 14 healthy volunteers, iohexol was administered intravenously as a reference GFR marker, and creatinine was introduced through a meat meal. A joint pharmacometric model was developed using dense plasma and urine sampling. Simulations were used to evaluate the effect of different creatinine volume of distribution (V_d) values on GFR estimation after acute kidney injury (AKI) and to assess the impact of limited sampling strategies on GFR and nCTS estimation. Pharmacokinetic parameters for iohexol and creatinine aligned with reported values, but a lower V_d of 41% of total body weight and a nCTS fraction of 31% relative to overall creatinine clearance were observed. Commonly used equations based on single-point creatinine measurement all overestimated GFR, with the Modification of Diet in Renal Disease (MDRD) equation performing best, followed by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation. Simulations demonstrate the effect of V_d estimate accuracy on detecting AKI from creatinine plasma concentrations only. Following low-dose iohexol administration, a single plasma sample at 5 hours and a urine sample from 0 to 5 hours provided accurate estimates of both GFR and nCTS using the joint model and enabled adequate correction for incomplete urine collection. This approach shows promise for assessing renal transporter activity based on estimated nCTS.