Effects of PQ912 on the Pharmacokinetics of Midazolam and Omeprazole
Condition: Healthy Volunteers; Pharmacologic Action
Study type: Interventional
Phase: Phase 1

Summary: 
      Midazolam is a rapid-acting benzodiazepine, with a short half-life (approximately 1.9 hours)
      and is primarily metabolised by CYP3A.

      Omeprazole is a selective proton pump inhibitor substrate used to reduce gastric acid
      secretion. Omeprazole is primarily metabolised by CYP2C19.

      Midazolam and omeprazole are both used as probe drugs in clinical pharmacology studies to
      evaluate clinical CYP3A and CYP2C19 drug interactions, respectively. Furthermore the EMA and
      the FDA guidance on drug interactions recommend the use of these drugs for such evaluations.

      The aim of this study is to assess the effect of PQ912 on the PK of midazolam and omeprazole.
      In vitro studies have demonstrated that PQ912 inhibits several CYP enzymes, including CYP3A4
      and CYP2C19 and at the expected exposure levels in patients, has the potential to inhibit
      these enzymes in-vivo. This study is therefore planned to investigate the potential changes
      in the PK of midazolam and omeprazole due to the effect of PQ912 at steady-state. In clinical
      practice it is likely that co-administration of PQ912 with other drugs that are metabolised
      via the CYP3A and/or CYP2C19 enzymes will occur. This study will provide important
      information for the requirement of dose adjustments or contraindications in these
      circumstances.
    

Detailed description: 
      This will be an open-label, crossover, fixed sequence study in healthy male subjects. Thirty
      six (36) subjects will participate in the study and will be enrolled as two groups of 18
      (Groups 1 and 2).

      If the PK data from Group 1 demonstrate a clinically important inhibition of the CYP3A4
      and/or CYP2C19 enzymes then the second optional group (Group 2) might be studied at a lower
      dose level of PQ912 .

      Each subject will participate in one treatment period, residing at the CRU from Day -1 (the
      day before dosing) to Day 7 (until after the last PK sampling occasion).

      All subjects will return for a post study visit 5 to 7 days after their final dose.

      Dose Regimen:

      Each subject will receive single oral doses of midazolam and omeprazole on the morning of Day
      1.

      On the morning of Day 2, all subjects will commence the multiple dose regimen for PQ912,
      which will continue for 5 days in total.

      Subjects in Group 1 and (if it necessary) in Group 2 will receive PQ912 twice daily (bid) on
      Days 2 to 6 inclusive and subjects in Group 2 will receive PQ912 bid on Days 2 to 6
      inclusive.

      On the morning of Day 6 subjects will be given single oral doses of midazolam and omeprazole
      co-administered with PQ912.
    

Intervention name(s): PQ912; Midazolam; Omeprazole
Intervention type(s): Drug; Drug; Drug
Intervention description(s): from day2 up to day6 twice daily oral dose of PQ912; single oral dose on day1 and day 6; single oral dose on day1 and day6
Other intervention name(s): Glutaminyl Cyclase Inhibitor; benzodiazepine; Proton pump inhibitor
Intervention MeSH terms: Midazolam; Omeprazole; Proton Pump Inhibitors
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: PQ912; Midazolam; Omeprazole; Pharmacokinetics; Drug Interaction