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Apr 5, 2021
  |  Presentation

Quantitative systems toxicology (QST) to investigate mechanisms contributing to clinical bilirubin elevations

Background:

Some patients treated with Drug X experienced clinically relevant elevations in serum bilirubin with concomitant ALT elevations, indicative of potentially severe liver injury (Hy’s Law cases). However, the interpretation is complicated if there is evidence that a compound directly alters bilirubin disposition, leading to bilirubin elevations absent liver injury. Distinguishing between these two possibilities is critical to inform drug development decisions. DILIsym®, a QST platform of drug‑induced liver injury (DILI), was used to investigate the interpretation of putative Drug X-related elevations in liver biomarkers.

Methods:

The initial investigation leveraged the well-characterized relationship among hepatocytes, ALT release, and ALT half-life to estimate the degree of hepatocyte loss that would account for measured elevations in liver biomarkers. Specifically, the magnitude of hepatocyte loss was inferred by approximating the clinical ALT profiles through imposed hepatocyte death1.  After simulated ALT profiles aligned with clinical data, simulations were analyzed to determine if hepatocyte death that recapitulated ALT profiles resulted in predicted bilirubin elevations similar to clinically measured bilirubin levels.

Secondly, the potential for Drug X‑mediated altered bilirubin disposition to account for observed bilirubin elevations was investigated2. A PBPK model was constructed to predict the exposure of Drug X. In vitro data delineating the effects of Drug X on bilirubin transporter expression and function as well as enzyme function were incorporated.  Simulations were performed by combining PBPK predictions for Drug X exposure with mechanistic bilirubin inhibition parameters derived from the in vitro assays in a simulated population (SimPops™).

Results:

Simulated hepatocyte loss that resulted in ALT profiles in line with clinical observations were not sufficient to yield clinically significant bilirubin elevations. Results suggest ALT and bilirubin elevations were decoupled and thus did not reflect severe liver injury.

Simulation results combining Drug X exposure and the mechanistic interaction of Drug X with bilirubin transporters and enzymes were consistent with timing for clinical bilirubin elevations but underpredicted the magnitude of elevations.  Although results underpredicted magnitude of bilirubin elevations, they suggested that altered bilirubin disposition had the potential to lead to clinically observed bilirubin elevations.  When newer data for Drug X effects on MRP2 expression were included, simulations predicted that a Drug X-mediated reduction in MRP2 expression could account for observed serum bilirubin elevations.  Reductions >50% in MRP2 expression were required for simulations to predict serum bilirubin > 2x ULN in some individuals in the SimPops.

Conclusions:

DILIsym investigations suggested that observed bilirubin elevations did not reflect serious liver injury and might be a result of altered bilirubin disposition. Initial mechanistic modeling suggested drug inhibition of bilirubin transporter and enzyme function alone was insufficient to account for the magnitude of elevations and provided impetus to consider a direct effect on transporter expression, providing additional insight into putative mechanisms for altered bilirubin disposition.

References:

  1. Howell, B. A. et al. A mechanistic model of drug-induced liver injury AIDS the interpretation of elevated liver transaminase levels in a phase I clinical trial. CPT Pharmacomet. Syst. Pharmacol. 3, e98 (2014).
  2. Yang, K. et al. Systems pharmacology modeling of drug-induced hyperbilirubinemia: Differentiating hepatotoxicity and inhibition of enzymes/transporters. Clin. Pharmacol. Ther. 101, 501–509 (2017).

To be presented at the FDA/CDER and AASLD 2021 DILI Conference XVIII, April 20-22nd.

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