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

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ClinicalTrials.gov Identifier: NCT02494830
Recruitment Status : Completed
First Posted : July 10, 2015
Last Update Posted : July 10, 2015
Sponsor:
Information provided by (Responsible Party):
University Medicine Greifswald

Tracking Information
First Submitted Date  ICMJE July 7, 2015
First Posted Date  ICMJE July 10, 2015
Last Update Posted Date July 10, 2015
Study Start Date  ICMJE August 2014
Actual Primary Completion Date September 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 9, 2015)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: July 9, 2015)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: July 9, 2015)
  • cumulative excretion into urine (Ae,urine) [ Time Frame: 24, 48, 72, 92 and 120 h after study medication ]
    of ketamine and norketamine
  • cumulative excretion into feces (Ae,feces) [ Time Frame: 24, 48, 72, 92 and 120 h after study medication ]
    of ketamine and norketamine
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Single Dose Administration of Ketamine 10, 20, 40 and 80 mg and 5 mg Solution for Infusion in 15 Healthy Subjects
Official Title  ICMJE 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
Brief Summary 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
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Healthy
Intervention  ICMJE 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
Study Arms  ICMJE
  • Experimental: ketamine 5 mg intravenous
    Intervention: Drug: Ketamine
  • Experimental: ketamine 10 mg oral
    Intervention: Drug: Ketamine
  • Experimental: ketamine 20 mg oral
    Intervention: Drug: Ketamine
  • Experimental: ketamine 40 mg oral
    Intervention: Drug: Ketamine
  • Experimental: ketamine 80 mg oral
    Intervention: Drug: Ketamine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 9, 2015)
15
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE October 2014
Actual Primary Completion Date September 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02494830
Other Study ID Numbers  ICMJE Ketamine_03_2014
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University Medicine Greifswald
Study Sponsor  ICMJE University Medicine Greifswald
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Werner Siegmund, Prof Department of Clinical Pharmacology
PRS Account University Medicine Greifswald
Verification Date July 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP