Pharmacokinetics, Metabolism and Analgesic Effects of Flupirtine
NCT ID: NCT01676246
Last Updated: 2012-08-30
Study Results
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Basic Information
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COMPLETED
PHASE1
36 participants
INTERVENTIONAL
2008-05-31
2009-06-30
Brief Summary
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Detailed Description
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The anticonvulsant drug retigabine, which chemical structure only slightly differs from flupirtine (aromatic ring instead of the pyrimidine ring), is subjected to intensive glucuronidation and N-acetylation in man. In-vitro, retigabine is a substrate of the recombinant uridine glucoronosyl transferase (UGT) 1A1, 1A3, 1A4 and 1A9. Disposition of retigabine, however, was not influenced by the frequent UGT1A1\*28 polymorphism (Gilbert-Meulengracht syndrome) whereas the polymorphism of the N-acetyltransferase 2 (NAT2) resulted in significant changes in retigabine disposition.
Similar to retigabine, the carbamate group of flupirtine is hydrolyzed by carboxyl esterases. The decarbamylated product undergoes N-acetylation to form the major metabolite D13223. This acetylation is catalyzed in-vitro both by recombinant human NAT2 and NAT1. Furthermore, relatively stable quinone diimines for flupirtine and D13223 as catalyzed by peroxidases were detectable in in-vitro experiments. After repeated oral administration of flupirtine in man, quinone diimines and glutathione adducts of them in the form of mercapturic acid conjugates were detected.
Therefore, we hypothesize, that highly reactive diimine radicals may appear as intermediates which are detoxified by conjugation with glutathione via a glutathione S-transferase (GST). Diimine intermediates are known to have high cell toxicity, genotoxicity and carcinogenicity as shown for the intermediates of acetaminophen. By analogy to acetaminophen, the GSTP1 might be the isoform that is involved also in detoxification of flupirtine intermediates.
According to our hypothesis, the net appearance of toxic intermediates with diimine structure in hepatocytes is dependent on the activity of NAT1/NAT2, UGTs and GSTP1. Because NAT2, UGT1A1 and GSTP1 are highly polymorphic enzymes, the risk of flupirtine hepatotoxicity may be dependent on the genotype of the subjects that are treated with the drug.
Our clinical study was initiated to confirm, whether polymorphisms of NAT2, UGT1A1 and GSTP1 may significantly influence disposition and analgesic effect of flupirtine and whether the genetic background is of risk for the appearance of toxic intermediates and its stable terminal conjugates.
Conditions
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Study Design
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RANDOMIZED
CROSSOVER
BASIC_SCIENCE
NONE
Study Groups
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flupirtine per os single dose
100 mg flupirtine per os, pharmacokinetics of flupirtine, induce delayed onset of muscle soreness (DOMS), electric pain measurement
100 mg flupirtine per os
Administration of 100 mg flupirtine per os (1 capsule Kadadolon®)
induce delayed onset of muscle soreness (DOMS)
The DOMS exercise protocol consists of two sets of 50 concentric/eccentric contractions of the calf muscles of one leg with a rest of 5 min in-between. The exercise is performed 22-26 h prior to medication. For pain measurements, muscle pain is stimulated by standing on tiptoes of one leg for 30 s, which requires a constriction of the affected calf muscles. The other leg is lifted and the subjects are allowed to hold on to a table to keep their balance. The pain intensity during this stimulation is then rated by means of a 10 cm visual analogue scale (VAS). The VAS is extended from "no pain" to "intolerable pain" with a precision of 1 mm. The stimulation is repeated with the other leg. The sequence of the legs is chosen randomly.
electric pain measurement
The method has been described to be sensitive to quantify analgesic opioid effects. Painful 5 Hz sine waves electrical stimuli (increase of intensity 0.2 mA/s, from 0 to 20 mA), which predominantly activate C-fibres, will be applied via two gold electrodes placed on the medial and lateral side of the distal phalangeal joint (middle finger of the left hand as default-testing site).
During testing, subjects keep a button continuously pressed until they find the pain intolerably and interrupt the current by releasing the button. The electrical current at which this occurred is defined as pain tolerance, the target parameter of this pain model. Each value of pain tolerance is the median of five subsequent measurements obtained at an interval of 1 min.
flupirtine intravenous
100 mg flupirtine intravenous, pharmacokinetics of flupirtine, induce delayed onset of muscle soreness (DOMS), electric pain measurement
100 mg flupirtine intravenous
Administration of 100 mg flupirtine intravenous (3 mg solution intravenously, 1 vial Kadadolon® inject)
induce delayed onset of muscle soreness (DOMS)
The DOMS exercise protocol consists of two sets of 50 concentric/eccentric contractions of the calf muscles of one leg with a rest of 5 min in-between. The exercise is performed 22-26 h prior to medication. For pain measurements, muscle pain is stimulated by standing on tiptoes of one leg for 30 s, which requires a constriction of the affected calf muscles. The other leg is lifted and the subjects are allowed to hold on to a table to keep their balance. The pain intensity during this stimulation is then rated by means of a 10 cm visual analogue scale (VAS). The VAS is extended from "no pain" to "intolerable pain" with a precision of 1 mm. The stimulation is repeated with the other leg. The sequence of the legs is chosen randomly.
electric pain measurement
The method has been described to be sensitive to quantify analgesic opioid effects. Painful 5 Hz sine waves electrical stimuli (increase of intensity 0.2 mA/s, from 0 to 20 mA), which predominantly activate C-fibres, will be applied via two gold electrodes placed on the medial and lateral side of the distal phalangeal joint (middle finger of the left hand as default-testing site).
During testing, subjects keep a button continuously pressed until they find the pain intolerably and interrupt the current by releasing the button. The electrical current at which this occurred is defined as pain tolerance, the target parameter of this pain model. Each value of pain tolerance is the median of five subsequent measurements obtained at an interval of 1 min.
flupirtine per os steady state
400 mg flupirtine per os, pharmacokinetics of flupirtine, electric pain measurement
400 mg flupirtine per os
Administration of 400 mg flupirtine (1 Kadadolon® S long retard tablet)
electric pain measurement
The method has been described to be sensitive to quantify analgesic opioid effects. Painful 5 Hz sine waves electrical stimuli (increase of intensity 0.2 mA/s, from 0 to 20 mA), which predominantly activate C-fibres, will be applied via two gold electrodes placed on the medial and lateral side of the distal phalangeal joint (middle finger of the left hand as default-testing site).
During testing, subjects keep a button continuously pressed until they find the pain intolerably and interrupt the current by releasing the button. The electrical current at which this occurred is defined as pain tolerance, the target parameter of this pain model. Each value of pain tolerance is the median of five subsequent measurements obtained at an interval of 1 min.
Interventions
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100 mg flupirtine intravenous
Administration of 100 mg flupirtine intravenous (3 mg solution intravenously, 1 vial Kadadolon® inject)
100 mg flupirtine per os
Administration of 100 mg flupirtine per os (1 capsule Kadadolon®)
400 mg flupirtine per os
Administration of 400 mg flupirtine (1 Kadadolon® S long retard tablet)
induce delayed onset of muscle soreness (DOMS)
The DOMS exercise protocol consists of two sets of 50 concentric/eccentric contractions of the calf muscles of one leg with a rest of 5 min in-between. The exercise is performed 22-26 h prior to medication. For pain measurements, muscle pain is stimulated by standing on tiptoes of one leg for 30 s, which requires a constriction of the affected calf muscles. The other leg is lifted and the subjects are allowed to hold on to a table to keep their balance. The pain intensity during this stimulation is then rated by means of a 10 cm visual analogue scale (VAS). The VAS is extended from "no pain" to "intolerable pain" with a precision of 1 mm. The stimulation is repeated with the other leg. The sequence of the legs is chosen randomly.
electric pain measurement
The method has been described to be sensitive to quantify analgesic opioid effects. Painful 5 Hz sine waves electrical stimuli (increase of intensity 0.2 mA/s, from 0 to 20 mA), which predominantly activate C-fibres, will be applied via two gold electrodes placed on the medial and lateral side of the distal phalangeal joint (middle finger of the left hand as default-testing site).
During testing, subjects keep a button continuously pressed until they find the pain intolerably and interrupt the current by releasing the button. The electrical current at which this occurred is defined as pain tolerance, the target parameter of this pain model. Each value of pain tolerance is the median of five subsequent measurements obtained at an interval of 1 min.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* sex and genetics: male and female genotyped for NAT2, UGT1A1 and GSTP1
* ethnic origin: Whites
* body weight: 19 - 27 kg/m²
* good health as evidenced by the results of the clinical examination, ECG, and the laboratory check-up, which are judged by the clinical investigator not to differ in a clinical relevant way from the normal state
* written informed consent
Exclusion Criteria
* existing or further obstructive lung disease (e.g. bronchial asthma)
* myasthenia gravis
* existing hepatic and renal diseases and/or pathological findings which might interfere with safety, pharmacodynamic effect and/or pharmacokinetics of the study drug
* existing gastrointestinal diseases and/or pathological findings which might interfere with safety, pharmacodynamic effect and/or pharmacokinetics of the study drug
* acute or chronic diseases which could affect drug absorption or metabolism
* history of any serious psychological disorder
* drug or alcohol dependence
* positive drug screening or -only in suspicious case- positive alcohol test
* smokers of 10 or more cigarettes per day
* positive screening results for HIV, HBV and HCV
* volunteers who are on a diet which could affect the pharmacokinetics of the drug (vegetarian)
* heavy tea or coffee drinkers (more than 1l per day)
* lactation and pregnancy test positive or not performed
* volunteers suspected or known not to follow instructions
* volunteers who are unable to understand the written and 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
* blood donation or other blood loss of more than 400 ml within the last 12 weeks prior to the start of the study
* 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
* any systemically available medication within 4 weeks prior to the intended first administration unless, because of the terminal elimination half-life, complete elimination from the body can be assumed for the drug and/or its primary metabolites (except oral contraceptives)
* repeated use of drugs during the last 4 weeks prior to the intended first administration, which can influence hepatic biotransformation (e.g. barbiturates, cimetidine, phenytoin, rifampicin)
* repeated use of drugs during the last 2 weeks prior to the intended first administration which affect absorption (e.g. laxatives, metoclopramide, loperamide, antacids, H2-receptor antagonists)
* intake of grapefruit containing food or beverages within 7 days prior to administration
* known allergic reactions to the active ingredients used or to constituents of the pharmaceutical preparation
* subjects with severe allergies or multiple drug allergies
18 Years
45 Years
ALL
Yes
Sponsors
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AWD.pharma GmbH & Co. KG
UNKNOWN
University Medicine Greifswald
OTHER
Responsible Party
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Prof. Werner Siegmund
Prof. Dr. W. Siegmund, MD
Locations
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Department of Clinical Pharmacology, Ernst-Moritz-Arndt-University Greifswald
Greifswald, Mecklenburg-Vorpommern, Germany
Countries
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Other Identifiers
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Flpmetab2008
Identifier Type: -
Identifier Source: org_study_id