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Background and Objectives <p>This study investigates the pharmacokinetics (PK) of entrectinib and its metabolite M5 (CYP3A4 substrates) in patients with hepatic impairment (HI) and applies physiologically based pharmacokinetic (PBPK) modelling to understand the observed changes mechanistically.</p> Method <p>After a single oral administration of entrectinib at 100 mg, measured plasma concentrations for entrectinib and M5 in control subjects and HI patients were compared to predictions made with Simcyp<sup>®</sup>. Model sensitivity analyses explored the possible reasons for mismatches to observed data. Reduced oral absorption due to lower bile salt (BS) levels in the intestinal lumen in hepatic impairment was examined.</p> Results <p>Physiologically based pharmacokinetic model simulations overestimated the 80% increase in entrectinib area under the plasma concentration curve between 0h to infinity (AUC<sub>inf</sub>) observed in patients with severe HI, predicting a &gt; 2-fold rise. Observed maximal plasma concentration (<i>C</i><sub>max</sub>) increased by 25% from controls to mild HI but decreased by 61% from mild to severe HI. Although the model predicted <i>C</i><sub>max</sub> within a 2-fold range, there was a trend to greater over-prediction with increasing HI severity. For M5, PBPK modelling did not capture the observed trends well. The <i>C</i><sub>max</sub> and AUC<sub>inf</sub> were overestimated in HI patients and the trend to&#xa0;reduction of <i>C</i><sub>max</sub> with minimal change in AUC<sub>inf</sub> with increasing severity of HI was not well captured.</p> <p>Decreasing Simcyp<sup>®</sup> default luminal BS concentrations by 2-, 6-, and 8.7-fold for mild, moderate, and severe HI improved the predictions for both entrectinib and M5.</p> Conclusion <p>Physiologically based pharmacokinetic model simulations tended to overestimate the observed moderate changes in entrectinib exposures due to HI. For improved prediction of poorly soluble lipophilic drugs like entrectinib there is a need for PBPK models of HI to account for additional pathophysiological changes such as reduced intestinal BS levels.</p> Trial Registration <p>NCT number: NCT04226833.</p>

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Clinical Exploration and Physiologically Based Modelling of the Impact of Hepatic Impairment on Entrectinib Pharmacokinetics

  • 期刊论文

  • 发表日期：

    2025年2月11日

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  • Agustos C. Ozbey,
  • Georgina Meneses-Lorente,
  • Brian Simmons,
  • Sam McCallum,
  • Pieter Annaert,
  • Neil Parrott,
  • Kenichi Umehara

摘要

Background and Objectives

This study investigates the pharmacokinetics (PK) of entrectinib and its metabolite M5 (CYP3A4 substrates) in patients with hepatic impairment (HI) and applies physiologically based pharmacokinetic (PBPK) modelling to understand the observed changes mechanistically.

Method

After a single oral administration of entrectinib at 100 mg, measured plasma concentrations for entrectinib and M5 in control subjects and HI patients were compared to predictions made with Simcyp®. Model sensitivity analyses explored the possible reasons for mismatches to observed data. Reduced oral absorption due to lower bile salt (BS) levels in the intestinal lumen in hepatic impairment was examined.

Results

Physiologically based pharmacokinetic model simulations overestimated the 80% increase in entrectinib area under the plasma concentration curve between 0h to infinity (AUCinf) observed in patients with severe HI, predicting a > 2-fold rise. Observed maximal plasma concentration (Cmax) increased by 25% from controls to mild HI but decreased by 61% from mild to severe HI. Although the model predicted Cmax within a 2-fold range, there was a trend to greater over-prediction with increasing HI severity. For M5, PBPK modelling did not capture the observed trends well. The Cmax and AUCinf were overestimated in HI patients and the trend to reduction of Cmax with minimal change in AUCinf with increasing severity of HI was not well captured.

Decreasing Simcyp® default luminal BS concentrations by 2-, 6-, and 8.7-fold for mild, moderate, and severe HI improved the predictions for both entrectinib and M5.

Conclusion

Physiologically based pharmacokinetic model simulations tended to overestimate the observed moderate changes in entrectinib exposures due to HI. For improved prediction of poorly soluble lipophilic drugs like entrectinib there is a need for PBPK models of HI to account for additional pathophysiological changes such as reduced intestinal BS levels.

Trial Registration

NCT number: NCT04226833.