Application of Individualized PBPK Modeling of Rate Data (iPBPK-R) to Evaluate the Effect of Hemodialysis On Nonrenal Clearance Pathways.

Franchetti, Yoko; Nolin, Thomas D

The aim of this study was to apply individualized, physiologically-based pharmacokinetic (iPBPK-R) modeling of 14 CO2 production rates measured by the erythromycin breath test (ERMBT) to characterize the effect of hemodialysis on the function of nonrenal clearance pathways in patients with end-stage renal disease (ESRD). Twelve patients previously received 14 C-erythromycin intravenously pre- and post-hemodialysis. Serial breath samples were collected after each dose over two hours. Eight PBPK parameters were co-estimated across periods while activity of CYP3A4 clearance was independently estimated for each period. Inhibition coefficients for OATP, P-gp, and MRP2 activities were also estimated. Nonrenal clearance parameter estimates were explored regarding sex differences, correlations with uremic toxins, and used in hierarchical cluster analysis (HCA). Relationships between the function of nonrenal clearance pathways and uremic toxin concentrations were explored. Mean CYP3A4 clearance increased by 2.2% post-hemodialysis. Uptake transporter activity was highly inter-variable across hemodialysis. Females had 22% and 30% higher median CYP3A4 activity than males pre- and post-hemodialysis, respectively. Exploratory HCA indicated that using both CYP3A4 and OATP activity parameters at pre- and post-HD best identifies heterogeneous patients. This is the first study to utilize the iPBPK-R approach to simultaneously estimate multiple in vivo nonrenal elimination pathways in individual patients with kidney disease and to assess the effect of hemodialysis. This article is protected by copyright. All rights reserved.