A clinical study to assess CYP1A2 and CYP3A4 induction by AZD7325, a selective GABA_A receptor modulator – an in vitro and in vivo comparison

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • AZD7325 is an orally administered, potent, selective gamma-amino-butyric acid (GABAA) a2,3 receptor modulator intended for the treatment of anxiety. • The induction effects of AZD7325 on CYP1A2 and CYP3A4 have not been systematically studied. WHAT THIS STUDY ADDS • The in vitro studies showed that AZD7325 was a moderate CYP1A2 inducer and potent CYP3A4 inducer. • The follow-up clinical studies in healthy volunteers demonstrated that the expected efficacious daily dose of AZD7325 only weakly induced the pharmacokinetics of the CYP3A4 sensitive substrate, midazolam, and had no effect on the pharmacokinetics of the CYP1A2 substrate, caffeine. There was no apparent change in AZD7325 exposure following co-administration of midazolam or caffeine compared with AZD7325 alone. • The study demonstrated that clinical exposure of the inducer plays a critical role in the determination of cytochrome P450 induction risk of a drug candidate. AIM(S) To investigate the potential of AZD7325 to induce CYP1A2 and CYP3A4 enzyme activities. METHODS Induction of CYP1A2 and CYP3A4 by AZD7325 was first evaluated using cultured human hepatocytes. The effect of multiple doses of 10 mg AZD7325 on the pharmacokinetics of midazolam and caffeine was then examined in healthy subjects. RESULTS The highest CYP1A2 and CYP3A4 induction responses were observed in human hepatocytes treated with 1 or 10 mM of AZD7325, in the range of 17.9%-54.9% and 76.9%-85.7% of the positive control responses, respectively. The results triggered the further clinical evaluation of AZD7325 induction potential. AZD7325 reached a plasma Cmax of 0.2 mM after 10 mg daily dosing to steady-state. AZD7325 decreased midazolam geometric mean AUC by 19% (0.81-fold, 90% CI 0.77, 0.87), but had no effect on midazolam Cmax (90% CI 0.82, 0.97). The mean CL/F of midazolam increased from 62 l h-1 (midazolam alone) to 76 l h-1 when co-administered with AZD7325. The AUC and Cmax of caffeine were not changed after co-administration of AZD7325, with geometric mean ratios (90% CI) of 1.17 (1.12, 1.23) and 0.99 (0.95, 1.03), respectively. CONCLUSIONS While AZD7325 appeared to be a potent CYP3A4 inducer and a moderate CYP1A2 inducer from in vitro studies, the expected efficacious dose of AZD7325 had no effect on CYP1A2 activity and only a weak inducing effect on CYP3A4 activity. This comparison of in vitro and in vivo results demonstrates the critical role that clinical exposure plays in evaluating the CYP induction risk of a drug candidate.

Population pharmacokinetic modelling to assess clinical drug-drug interaction between AZD7325 and midazolam

“…Despite the limitations, the induction effect and concentration of the inducing agent could follow a linear relationship within a limited concentration range. CYP3A4 enzyme activities did increase linearly as the increase in AZD7325 concentration in the range of 0·01–1 μ m in a hepatocyte induction study . Considering the C max of 0·2 μ m after repeated oral dosing of 10 mg AZD7325, it is reasonable to assume a linear relationship between induction effect and AZD7325 concentration in the analysis.…”

“…The design of a DDI study between AZD7325 and midazolam has been described in detail elsewhere . Briefly, a total of 24 healthy male subjects were enrolled and 23 completed the study.…”

“…AZD7325, a selective gamma‐amino‐butyric acid (GABA A ) α2, 3 receptor modulator, was under development for the treatment of anxiety . The dedicated clinical studies in healthy subjects indicated that 10 mg daily doses of AZD7325 at steady state only weakly affected the pharmacokinetics of the CYP3A4‐sensitive substrate, midazolam . The apparent midazolam clearance increased by ~23% with the treatment of multiple doses of AZD7325 …”

The central nervous system effects of the partial GABA‐Aα2,3‐selective receptor modulator AZD7325 in comparison with lorazepam in healthy males

“…AZD7325, 4‐amino‐8‐(2‐fluoro‐6‐methoxy‐phenyl)‐N‐propyl‐cinnoline‐3‐carboxamide , is a novel partial subtype‐selective GABA‐Aα 2,3 receptor modulator, which is in development for anxiety disorders. In vitro AZD7325 demonstrated functional specificity for the GABA‐Aα 2 and GABA‐Aα 3 receptor subtypes.…”

Synthesis of C‐14 labeled GABAA α2/α3 selective partial agonists and the investigation of late‐occurring and long‐circulating metabolites of GABAA receptor modulator AZD7325

“…CYP3A4 is the major hepatic and intestinal CYP isoform in humans and plays a role in approximately 50% of clinically used drugs . In previous studies, induction and drug‐drug interactions for AZD7325 have been assessed . Herein, we report the preparation and use of radiolabeled compounds to understand the metabolism more thoroughly.…”