AZD1390 was identified as a highly potent, selective, small molecule inhibitor of ataxia telangiectasia mutated (ATM) kinase for use in combination with irradiation in the treatment of Glioblastoma Multiforme (GBM). Metabolism profiling in human hepatocytes and cytosol indicated that AZD1390 is a substrate for aldehyde oxidase (AO). Recognising the historic failure of several AO substrates as therapeutics due to high first pass hepatic extraction and subsequently low oral bioavailability, AZD1390 was benchmarked against a range of known AO substrates in human liver cytosol (HLC) and hepatocytes and this data established AZD1390 clearance (Cl) was likely to be high, approaching liver blood flow. PBPK based simulations of animal PK predicted a high human volume of distribution (Vss) for this monobase, (∼19 L/kg) which, together with a predicted complete fraction absorbed, indicated an acceptable human oral profile to support sufficient target engagement was achievable. Whilst acknowledging a degree of uncertainty and risk for this AO substrate, AZD1390 was progressed into the clinic to assess human exposure. Analysis of plasma from patients following a single oral AZD1390 dose of 40 mg confirmed the presence of a major AO dependent metabolite (M10) at comparable levels to AZD1390. The clinical oral PK of AZD1390 was comparable with the simulated high clearance (Clb 15-20 mL/min/kg) profiles and supported continued progression of AZD1390. Furthermore, AZD1390 has shown brain penetrance in healthy volunteer positron emission tomography (PET) studies and is currently in GBM clinical trials. This work demonstrates AO substrates with suitable properties can achieve acceptable human PK.
Author: Nicola Colclough a, Alexandra L. Orton a, Scott Martin a,Martin Wild a, Venkatesh Pilla Reddy a, Eva Lenz b, Roshini Markandu a, Joanne Wilson a, Chunling Fan c, Julian Potter c, David Dai c, Christina Chan a, Jennie Roberts a, Aixiang Xue d, Petar Pop-Damkov e, Andy Sykes a, Barry Jones a, Thomas A. Hunt b, Kurt Pike b, Dermot F. McGinnity a. Drug Metabolism and Disposition
