Drug clearance by aldehyde oxidase: can we avoid clinical failure?

Abstract

1. Despite increased awareness of aldehyde oxidase (AO) as a major drug-metabolising enzyme, predicting the pharmacokinetics of its substrates remains challenging. Several drug candidates have been terminated due to high clearance, which were subsequently discovered to be AO substrates. Even retrospective extrapolation of human clearance, from models more sensitive to AO activity, often resulted in underprediction.

2. The questions of the current work thus were: Is there an acceptable degree of in vitro AO metabolism that does not result in high in vivo human clearance? And, if so, how can this be predicted?

3. We built an in vitro/in vivo correlation using known AO substrates, combining multiple in vitro parameters to calculate the blood metabolic clearance mediated by AO (CLb_AO). This value was compared with observed blood clearance (CLb_-obs), establishing cut-off CLb_AO values, to discriminate between low and high CLb_-obs. The model was validated using additional literature compounds, and CLb_-obs was predicted in the correct category.

4. This simple, categorical, semi-quantitative yet multi-factorial model is readily applicable in drug discovery. Further, it is valuable for high-clearance compounds, as it predicts the CLb group, rather than an exact CLb value, for the substrates of this poorly-characterised enzyme.

Keywords:

• Aldehyde oxidase
• drug metabolism
• oxidation
• pharmacokinetics
• inhibition
• clearance
• IVIVC
• fraction-metabolised

Acknowledgments

We sincerely thank Oriana Laforgia, Prabha Peramuhendige, Syeda Shah, Jean-Nicolas Lodewyckx and Magdalena Kierkowicz for their technical support with in vitro experiments, as well as Dr Nenad Manevski for his extensive contribution to the discussions that produced this work. We would also like to thank Dr Teresa de Haro Garcia for supporting the synthesis of Lu AF09535, Lloyd King for his expert input on metabolite data analysis and Dr Beth Williamson for her considered review of the manuscript. We acknowledge Cyprotex Discovery Limited (UK) for the protein-binding and B:P assays. Last, but by far not least, we would like to sincerely thank Claude Delatour for his expertise, UPLC-MS analysis and unfailing support throughout the entirety of this work. You are probably enjoying your well-deserved retirement right now, but we greatly miss you.

Disclosure statement

The authors are employees of UCB or Janssen Pharmaceutical Companies of Johnson & Johnson and may have access to share options.