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Abstract: TH-PO356

Application of Individualized Physiologically Based Pharmacokinetic Modeling of Rate Data (iPBPK-R) to Estimate the Effect of Hemodialysis on Nonrenal Clearance Pathways

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Franchetti, Yoko, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Nolin, Thomas D., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background

We previously developed an individualized physiologically-based pharmacokinetic modeling approach using rate data (iPBPK-R) to differentiate contributions of nonrenal metabolic and transport pathways to the disposition of the non-specific probe drug erythromycin. The objectives of the current work were (1) to differentially estimate contributions of nonrenal clearance pathways to erythromycin in patients with ESRD, (2) to investigate the effect of hemodialysis (HD) on these pathways, and (3) to explore the relationship between parameter estimates and uremic toxin concentrations.

Methods

Twelve patients with ESRD received 14C-erythromycin (0.074 mmol IV) pre- and again post-HD and 11 breath samples were collected over 2 hours after each dose. iPBPK-R was applied to measured 14CO2 production rates. Eight PBPK parameters were co-optimized between pre- and post-HD periods within patients while activity of CYP3A4 clearance was independently estimated. Inhibitory coefficients of uptake transporters (i.e., OATP) were also estimated. Nonrenal clearance parameter estimates were compared pre- vs post-HD and by gender. As exploratory analysis, the parameter estimates were correlated with uremic solutes and used in hierarchical cluster analysis (HCA). Optimizations were run on the Bridges supercomputer (PSC via NSF XSEDE).

Results

Seven compartments with OATP uptake and CYP3A4 clearance were modeled. Mean relative increase in CYP3A4 clearance pre- vs post-HD within individual patients was 12% which was not statistically significant (p=0.06). However, males had 16% and 19.3% lower median CYP3A4 activity than females pre- (p=0.001) and post-HD (p=0.005), respectively. The estimated inhibition coefficient of uptake transport did not differ between pre- and post-HD (p=0.129). A sub-cluster of two patients with more improved CYP3A4 activity at post-HD (9.4% increase) was identified compared to the other patients (0.59% increase). β-2 microglobulin was inversely correlated with CYP3A4 activity in males pre- (Spearman r=-0.79, p=0.04) but not post-HD.

Conclusion

iPBPK-R is a novel tool to estimate nonrenal clearance parameters within individuals and to explore the effect of HD and uremic toxins on drug disposition in patients with ESRD. Further work is required to validate the i-PBPK-R based results.

Funding

  • Other NIH Support