Single Dose Administration of Ketamine 10, 20, 40 and 80 mg and 5 mg Solution for Infusion in 15 Healthy Subjects

July 9, 2015 updated by: University Medicine Greifswald

Comparative Bioavailability Study of Ketamine and Norketamine After Single Dose Administration of Ketamine 10, 20, 40 and 80 mg Prolonged Release Tablets in Fasting State and 5 mg Ketamine Solution for Infusion in 15 Healthy Subjects in Serum, Urine and Feces

This study is designed for descriptive pharmacokinetic characterization of ketamine and norketamine in serum, urine and feces after oral single dose administration of a new developed prolonged release tablet formulation containing 10, 20, 40 and 80 mg ketamine under fasting conditions and for descriptive pharmacokinetic characterization of ketamine and norketamine in serum, urine and feces after intravenous single dose administration of 5 mg ketamine solution for infusion within 30 min

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Ketamine, a cyclohexanone derivative, is a non-barbiturate anesthetic agent which has been available in clinical practice for more than 40 years. Ketamine was first synthesized in 1962 and patented in Belgium in 1963. Ketamine, a potent non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has a recognized unique therapeutic value in human and veterinary medicine as an anesthetic with analgesic properties. Ketamine is considered as one of the World Health Organisation (WHO) essential drugs for the management of refractory pain.

Ketamine is widely used for the induction and maintenance of general anesthesia, usually in combination with a sedative and if required a muscle relaxant. When used as an intravenous (i.v.) or intra-muscular (i.m.) injection, ketamine is best suited for short procedures. With additional doses, or by i.v. infusion, ketamine can be used for longer procedures. Due to its pharmacodynamic properties, important clinical applications are mainly brief diagnostic ones and surgical procedures in paediatric patients and ambulatory anesthesia, treatment of burn patients, obstetrics, and for the induction and maintenance of anesthesia in trauma victims, hypovolemic patients, patients with septic or cardiogenic shock, and patients with pulmonary diseases. Other uses include sedation in the intensive care setting, and analgesia particularly in emergency medicine as well as treatment of bronchospasm / asthma. However, the use of ketamine for humans in the EU is restricted to special indications, due to the occurrence of emergence reactions. Outside the EU, its ease of use gives ketamine a major advantage under difficult circumstances (developing countries and remote areas).

For therapeutic purposes, ketamine is usually administered intravenously (i.v.) or intramuscularly (i.m.). Its hydrochloride salt is marketed under many brand names such as Ketanest, Ketalar, or Ketaset. Ketamine is a chiral compound. While most marketed ketamine preparations are racemic mixtures of R-(-)-ketamine and S-(+)-ketamine (1:1), formulations containing only the enantiomer S-(+)-ketamine are also commercially available (e.g. Ketanest® S, Pfizer Pharma GmbH). S-(+)-ketamine is approximately four times more potent than R-(-)-ketamine and twice as potent as the racemic mixture.

It is well-known that ketamine exerts analgesic effects at subanesthetic doses. Therefore, during the past 15-20 years, ketamine has been used as an analgesic in a wide range of pain settings, including acute (e.g. post-operative pain, pain during dental procedures) and chronic pain (e.g. central or peripheral neuropathic pain, cancer pain) conditions.

Although the drug is only approved for intramuscular injection and intravenous injection or infusion, ketamine is frequently used via other routes of administration, such as subcutaneous (s.c.) injection or infusion, rectal, oral, intranasal, transdermal (patch), intrathecal or epidural administration. Considering that no oral formulation is approved, the marketed solution for injection/infusion or an extemporaneous preparation was used in clinical studies investigating the efficacy of orally administered ketamine. For clinical (off-label) use, the solution for injection/infusion is generally employed for oral treatment.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
15

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
    • Mecklenburg-Vorpommern
      • Greifswald, Mecklenburg-Vorpommern, Germany, 17487
        • Department of Clinical Pharmacology, Ernst-Moritz-Arndt-University Greifswald

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 45 years (Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • age: 18 - 45 years
  • sex: male or female
  • ethnic origin: Caucasian
  • body mass index: > 18.5 kg/m² and < 30 kg/m²
  • good health as evidenced by the results of the clinical examination, ECG, and the laboratory check-up, which will be judged by the clinical investigator not to differ in a clinically relevant way from the normal state
  • heart frequency between 50 and 90 bpm
  • blood pressure between 140 and 100 systolic and 90 and 60 diastolic
  • written informed consent

Exclusion Criteria:

  • hepatic and renal diseases and/or pathological findings, which might interfere with pharmacokinetics of the study medication
  • existing cardiovascular or haematological diseases and/or pathological findings, which might interfere with the drug's safety, tolerability and/or pharmacokinetics (e.g. tachycardia > 90 bpm, bradycardia < 50 bpm, ischemic heart disease like angina pectoris instabilis or myocardial infarction in the last 6 months, hypertension > 140/90 mm Hg)
  • gastrointestinal diseases and/or pathological findings (e.g. stenoses), which might interfere with pharmacokinetics of the study medication
  • hypersensitivity to the active ingredient ketamine or any of the excipients
  • (pre-) eclampsia
  • poor or untreated hyperthyreosis
  • increased intracranial pressure
  • glaucoma or perforating eye injury
  • drug or alcohol dependence
  • positive drug or alcohol screening
  • smokers of 10 or more cigarettes (or equivalent) per day
  • positive results in HIV, HBV or HCV screenings
  • volunteers, who are on a diet, which could affect the pharmacokinetics of the drug
  • heavy tea or coffee drinkers (more than 1L per day)
  • lactation, pregnancy test positive or not performed or women of child-bearing age without safe contraception, as described on page 18, ch. 7.4.1. (Note for Guidance on Non-clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceutical (CPMP/ICH/286/95 modifications))
  • volunteers, suspected or known, not to follow instructions of the clinical investigators
  • volunteers, who are unable to understand the written or verbal instructions, in particular regarding the risks and inconveniences, they will be exposed to, as a result of their participation in the study
  • volunteers, liable to orthostatic dysregulation, fainting, or blackouts
  • participation in a clinical trial during the last 3 months prior to the start of the study
  • less than 14 days after last acute disease
  • less than 3 months after last blood donation
  • intake of thyroid hormones or sympathomimetics
  • any medication within 4 weeks prior to the intended first administration of the study medication, which might influence functions of the gastrointestinal tract (e.g. laxatives, metoclopramide, loperamide, antacids, H2-receptor antagonists, proton pump inhibitors, anticholinergics)
  • any other medication within two weeks prior to the first administration of the study medication, but at least 10-time the half-live of the respective drug (except oral contraceptives)
  • intake of grapefruit containing food or beverages within 14 days prior to administration of the study medication
  • intake of poppy seed containing food or beverages within 14 days prior to administration of the study medication
  • known allergic reactions to the active ingredients used or to constituents of the study medication

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: ketamine 5 mg intravenous
Drug: Ketamine
Intravenous infusion of 5 mg ketamine solution, diluted in 240 ml 0.9% saline within 30 min under fasting conditions on study day 1 and oral administration of one prolonged release tablet ketamine together with 240 ml table water under fasting conditions with increased dose (10, 20, 40 and 80 mg) and at least 7 days wash-out between the study days
Experimental: ketamine 10 mg oral
Drug: Ketamine
Intravenous infusion of 5 mg ketamine solution, diluted in 240 ml 0.9% saline within 30 min under fasting conditions on study day 1 and oral administration of one prolonged release tablet ketamine together with 240 ml table water under fasting conditions with increased dose (10, 20, 40 and 80 mg) and at least 7 days wash-out between the study days
Experimental: ketamine 20 mg oral
Drug: Ketamine
Intravenous infusion of 5 mg ketamine solution, diluted in 240 ml 0.9% saline within 30 min under fasting conditions on study day 1 and oral administration of one prolonged release tablet ketamine together with 240 ml table water under fasting conditions with increased dose (10, 20, 40 and 80 mg) and at least 7 days wash-out between the study days
Experimental: ketamine 40 mg oral
Drug: Ketamine
Intravenous infusion of 5 mg ketamine solution, diluted in 240 ml 0.9% saline within 30 min under fasting conditions on study day 1 and oral administration of one prolonged release tablet ketamine together with 240 ml table water under fasting conditions with increased dose (10, 20, 40 and 80 mg) and at least 7 days wash-out between the study days
Experimental: ketamine 80 mg oral
Drug: Ketamine
Intravenous infusion of 5 mg ketamine solution, diluted in 240 ml 0.9% saline within 30 min under fasting conditions on study day 1 and oral administration of one prolonged release tablet ketamine together with 240 ml table water under fasting conditions with increased dose (10, 20, 40 and 80 mg) and at least 7 days wash-out between the study days

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
bioavailability (F)
Time Frame: before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12 16, 24 36, 48, 60 h after study medication
of ketamine
before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12 16, 24 36, 48, 60 h after study medication

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
area under the concentrations-time curve (AUC)
Time Frame: before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12 16, 24 36, 48, 60 h after study medication
of ketamine and norketamine
before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12 16, 24 36, 48, 60 h after study medication
maximum concentration (Cmax) of the concentrations-time curve
Time Frame: before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12 16, 24 36, 48, 60 h after study medication
of ketamine and norketamine
before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12 16, 24 36, 48, 60 h after study medication
time point of maximum concentration (Tmax)
Time Frame: before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12 16, 24 36, 48, 60 h after study medication
of ketamine and norketamine
before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12 16, 24 36, 48, 60 h after study medication
terminal half-life (T1/2)
Time Frame: before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12 16, 24 36, 48, 60 h after study medication
of ketamine and norketamine
before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12 16, 24 36, 48, 60 h after study medication
volume of distribution at steady state (Vss)
Time Frame: before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 h after study medication
of ketamine
before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 h after study medication
renal clearance (CLR)
Time Frame: before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12 16, 24 36, 48, 60 and 72 h after study medication
of ketamine
before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12 16, 24 36, 48, 60 and 72 h after study medication
metabolic clearance (CLM)
Time Frame: before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 92 and 120 h after study medication
of ketamine
before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 92 and 120 h after study medication
intestinal clearance (CLintestinal)
Time Frame: before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 92 and 120 h after study medication
of ketamine
before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 92 and 120 h after study medication
mean residence time (MRT)
Time Frame: before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12 16, 24 36, 48, 60 h after study medication
of ketamine
before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12 16, 24 36, 48, 60 h after study medication
mean absorption time (MAT)
Time Frame: before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12 16, 24 36, 48, 60 h after study medication
of ketamine
before and 10, 20, 30, 40, 50 min and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12 16, 24 36, 48, 60 h after study medication

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
cumulative excretion into urine (Ae,urine)
Time Frame: 24, 48, 72, 92 and 120 h after study medication
of ketamine and norketamine
24, 48, 72, 92 and 120 h after study medication
cumulative excretion into feces (Ae,feces)
Time Frame: 24, 48, 72, 92 and 120 h after study medication
of ketamine and norketamine
24, 48, 72, 92 and 120 h after study medication

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University Medicine Greifswald

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
August 1, 2014

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 1, 2014

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
October 1, 2014

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 7, 2015

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 9, 2015

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 10, 2015

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 10, 2015

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 9, 2015

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • Ketamine_03_2014

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