title: 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: BACKGROUND
  • AZD7325 is an orally administered, potent, selective gamma-amino-butyric acid (GABA(A) ) α2,3 receptor modulator intended for the treatment of anxiety. • The induction effects of AZD7325 on CYP1A2 and CYP3A4 have not been systematically studied.
  
  
  CONCLUSIONS
  • 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.
  
  
  OBJECTIVE
  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 µm 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 C(max) of 0.2 µm 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 C(max) (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 C(max) 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.
authors: Clinical Pharmacology Science DMPK Clinical Neuroscience, AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850, USA. diansong.zhou@astrazeneca.com
authors: Diansong
authors: D
authors: Zhou
authors: Maria
authors: M
authors: Sunzel
authors: Maria D
authors: MD
authors: Ribadeneira
authors: Mark A
authors: MA
authors: Smith
authors: Dhaval
authors: D
authors: Desai
authors: Jianrong
authors: J
authors: Lin
authors: Scott W
authors: SW
authors: Grimm
mesh_terms: D000293:Adolescent; D000328:Adult; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D015153:Blotting, Western; D002110:Caffeine / Q000493:pharmacokinetics / Q000494:pharmacology; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000493:pharmacokinetics / Q000494:pharmacology; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis* / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D004347:Drug Interactions; D018757:GABA Modulators / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics / Q000494:pharmacology; D008875:Middle Aged; D012333:RNA, Messenger; D011963:Receptors, GABA-A / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: C576237:4-amino-8-(2-fluoro-6-methoxy-phenyl)-N-propylcinnoline-3-carboxamide; D014151:Anti-Anxiety Agents; D000697:Central Nervous System Stimulants; D018757:GABA Modulators; D006574:Heterocyclic Compounds, 2-Ring; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D002110:Caffeine; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam