PXB-mouse® was used to assess glucuronide formation and pharmacokinetics in human hepatocytes in vivo, as published by Phenex Pharmaceuticals AG team in ACS Medicinal Chemistry Letters “Discovery of Hydroxyamidine Based Inhibitors of IDO1 for Cancer Immunotherapy with Reduced Potential for Glucuronidation”.

Steeneck C. et al. [1] describes the optimization of cancer immunotherapy candidate with the need to reduce its potential for glucuronidation (phase II metabolism), and PXB-mouse® (chimeric mouse with humanized liver) was used during one of the final stages of such an optimization. Clinical data with epacadostat (investigational drug for cancer inhibiting IDO1 – an immune modulating enzyme indoleamine-2,3-dioxygenase-1) showed that hydroxyamidine based inhibitors are extensively glucuronidated in humans. In vitro data identified UGT1A9 (an isoform of UDP-glucuronosyltransferase) as the major involved enzyme.

Schematic overview of the glucuronidation reaction catalysed by UGT enzymes

Schematic overview of the glucuronidation reaction catalysed by UGT enzymes. Image credits to https://www.nature.com/articles/s41416-019-0722-0

Glucuronidation contribution to the response and resistance to cancer therapies is known for a long time. Studies of active metabolites of anti-cancer drugs indicate that UGT activity could significantly influence drug sensitivity and efficacy [2].

To make the evaluation of hepatic metabolic activity closer to human in vivo conditions, PXB-mice were used to investigate in details the pharmacokinetics (PK) of the most promising compound 24 with an emphasis on human glucuronidation. The reason for the model selection was the fact that livers are highly populated with human hepatocytes and that the major human drug metabolizing enzymes and transporters are active in the liver.

The pharmacokinetics of compound 24 vs. epacadostat in PXB-mice
The pharmacokinetics of compound 24 vs. epacadostat in PXB-mice

The comparative results of the most promising compound from the publication, compound 24, benchmarked against epacadostat showed significantly higher ratio of [AUC glucuronide]/[AUC parent]. (AUC is the area under the curve, and it reflects the actual body exposure to drug after administration of a dose of the drug.) Cmax was also few folds higher. So, the compound 24 had a significantly improved PK profile over epacadostat in PXB-mice with regard to hydroxyamidine glucuronidation.

Thus, PXB-mouse® once again is proven to be a useful tool for PK investigation of cancer leads in development, where glucuronidation process is an important factor in drug metabolism.

More publications with PXB-mouse and PXB-cells use for drug metabolism studies can be found here.

References

[1] Steeneck C. et al. “Discovery of Hydroxyamidine Based Inhibitors of IDO1 for Cancer Immunotherapy with Reduced Potential for Glucuronidation” ACS Med Chem Lett 11 (2), 179-187 (2020).

[2] Allain E.P. et al. “Emerging roles for UDP-glucuronosyltransferases in drug resistance and cancer progression” Br J Cancer 122, 1277–1287 (2020).

The summary of the publication is prepared by S. Sapelnikova