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Effects of PQ912 on the Pharmacokinetics of Midazolam and Omeprazole

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ClinicalTrials.gov Identifier: NCT02190708
Recruitment Status : Completed
First Posted : July 15, 2014
Last Update Posted : October 21, 2015
Sponsor:
Collaborator:
Covance
Information provided by (Responsible Party):
Probiodrug AG

Brief 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.


Condition or disease Intervention/treatment Phase
Healthy Volunteers Pharmacologic Action Drug: PQ912 Drug: Midazolam Drug: Omeprazole Phase 1

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: A Phase I, Open Label Study to Assess the Effects of PQ912 on the Pharmacokinetics of Midazolam and Omeprazole in Healthy Male Subjects
Study Start Date : June 2014
Actual Primary Completion Date : June 2014
Actual Study Completion Date : August 2014

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: PQ912 & Midazolam & Omeprazole
day2 - day6 800mg PQ912 twice per day po day1 / day6 2.5 mg Midazolam once per day day1 / day6 20 mg Omeprazole once per day
Drug: PQ912
from day2 up to day6 twice daily oral dose of PQ912
Other Name: Glutaminyl Cyclase Inhibitor

Drug: Midazolam
single oral dose on day1 and day 6
Other Name: benzodiazepine

Drug: Omeprazole
single oral dose on day1 and day6
Other Name: Proton pump inhibitor




Primary Outcome Measures :
  1. Effect of PQ912 at steady state on pharmacokinetic profile of Omeprazole and Midazolam [ Time Frame: from day 1 up to day 6 ]
    Serial blood samples on day 1 and day 6 from predose up to 24 hours postdose


Secondary Outcome Measures :
  1. Safety and tolerability of PQ912 in terms of Adverse Events Assessments when coadministered with Midazolam and Omeprazol [ Time Frame: day-1 up to day 6 and post dose visit ]
    Safety profile in terms of Adverse Events Assessments

  2. Safety and tolerability in terms of vital signs (blood pressure, pulse rate, respiration rate, Body temperature) [ Time Frame: from baseline up to end of study visit (2 weeks after first treatment) ]
  3. Safety and Tolerability by assessing changes in electrocardiogram (ECG) parameters [ Time Frame: from baseline up to end of study visit (2 weeks after first treatment) ]
  4. Safety and tolerability in terms of lab tests assessment (hematology, Serum biochemistry, serology, urinalysis) [ Time Frame: from baseline up to end of study visit (2 weeks after first treatment) ]


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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • males
  • of any ethnic origin
  • between 18 and 55 years of age
  • body mass index (BMI) between 18.0 and 32.0 kg/m2 inclusive
  • body weight between 50 kg and 100 kg inclusive
  • must be in good health,
  • will have given written informed consent and to abide by the study restrictions

Exclusion Criteria:

  • history of any clinically significant disease or disorder which, in the opinion of the Investigator, may put the subject at risk because of participation in the study, may influence the results, or may limit the subject's ability to participate in the study
  • history or presence of gastrointestinal, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs
  • active participation in a clinical study or participation in a clinical study investigating a new chemical entity within 3 months or 5 half-lives (whichever is longer prior to first dose)
  • clinically significant illness within 4 weeks of the start of the dose administration

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02190708


Locations
United Kingdom
Covance Clinical Research Unit Ltd
Leeds, United Kingdom, LS2 9LH
Sponsors and Collaborators
Probiodrug AG
Covance
Investigators
Principal Investigator: Joseph Chiesa, MD, Dr Covance

Responsible Party: Probiodrug AG
ClinicalTrials.gov Identifier: NCT02190708     History of Changes
Other Study ID Numbers: 1002308-8302860
2014-001883-36 ( EudraCT Number )
First Posted: July 15, 2014    Key Record Dates
Last Update Posted: October 21, 2015
Last Verified: July 2014

Keywords provided by Probiodrug AG:
PQ912
Midazolam
Omeprazole
Pharmacokinetics
Drug Interaction

Additional relevant MeSH terms:
Midazolam
Omeprazole
Proton Pump Inhibitors
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anti-Ulcer Agents
Gastrointestinal Agents
Enzyme Inhibitors