Achieving human brain exposure with the oral ataxia-telangiectasia mutated kinase inhibitor AZD1390, a substrate of aldehyde oxidase

AZD1390 was identified as a highly potent, selective, small-molecule inhibitor of ataxia-telangiectasia mutated kinase for use in combination with irradiation in the treatment of glioblastoma multiforme. Metabolism profiling in human hepatocytes and cytosol indicated that AZD1390 is a substrate for aldehyde oxidase (AO). Recognizing the historic failure of several AO substrates as therapeutics due to high first-pass hepatic extraction and subsequent low oral bioavailability, AZD1390 was benchmarked against a range of known AO substrates in human liver cytosol and hepatocytes. This data established AZD1390 clearance was likely to be high, approaching liver blood flow. Physiologically based pharmacokinetic (PBPK) simulations of animal PK predicted a high human volume of distribution for this monobase (∼19 L/kg). Together with a predicted complete fraction absorbed, this 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 to the simulated high clearance (15-20 mL/min/kg) profiles and supported continued progression of AZD1390. Furthermore, AZD1390 has shown brain penetrance in healthy volunteer positron emission tomography studies and is currently in glioblastoma multiforme clinical trials. This work demonstrates AO substrates with suitable properties can achieve acceptable human PK. SIGNIFICANCE STATEMENT: Several aldehyde oxidase (AO) substrates have failed in early clinical development due to low oral bioavailability. This case example demonstrates that despite the lack of relevant translational pharmacokinetics information from animals, via careful human in vitro benchmarking, certain AO substrates with suitable properties can be progressed and generate acceptable oral clinical pharmacokinetics. AZD1390 is a successful case example of prosecuting an AO substrate in the clinic after many documented failures.