In vitro assessment of metabolic drug–drug interaction potential of AZD2624, neurokinin-3 receptor antagonist, through cytochrome P₄₅₀ enzyme identification, inhibition, and induction studies

Abstract

1. AZD2624 was pharmacologically characterized as a NK3 receptor antagonist intended for treatment of schizophrenia. The metabolic drug–drug interaction potential of AZD2624 was evaluated in in vitro studies.

2. CYP3A4 and CYP3A5 appeared to be the primary enzymes mediating the formation of pharmacologically active ketone metabolite (M1), whereas CYP3A4, CYP3A5, and CYP2C9 appeared to be the enzymes responsible for the formation of the hydroxylated metabolite (M2). The apparent K_m values were 1.5 and 6.3 µM for the formation of M1 and M2 in human liver microsomes, respectively.

3. AZD2624 exhibited an inhibitory effect on microsomal CYP3A4/5 activities with apparent IC₅₀ values of 7.1 and 19.8 µM for midazolam and testosterone assays, respectively. No time-dependent inactivation of CYP3A4/5 activity (midazolam 1′-hydroxylation) by AZD2624 was observed. AZD2624 demonstrated weak to no inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

4. AZD2624 was not an inducer of CYP1A2 or CYP2B6. Although AZD2624-induced CYP3A4 activity in hepatocytes, the potential of AZD2624 to cause inductive drug interactions of this enzyme was low at relevant exposure concentration.

5. Together with targeted low efficacious concentration, the results of this study demonstrated AZD2624 has a relatively low metabolic drug–drug interaction potential towards co-administered drugs. However, metabolism of AZD2624 might be inhibited when co-administrated with potent CYP3A4/5 inhibitors.

Keywords::

• AZD2624
• CYP enzyme identification
• enzyme kinetics
• CYP inhibition
• CYP induction

Acknowledgements

The authors thank Frank Morris and colleagues at AstraZeneca for analytical supports and scientists at CellzDirect for their technical support in induction assessments. The authors also thank Mark Powell, James Kang, Hui Xiong and Lindsay Hinkley for synthesis of test compounds

Declaration of interest

Primary employment by AstraZeneca (Y.L., D.Z., P.D.; T.R.S, S.W.G) and primary employment by CellzDirect (S.S.F.).