Effects of 500 mg Immediate Release and Extended Release Methylnaltrexone on Loperamide-induced Delay of the Oro-cecal and Whole-gut Transit Time in Healthy Subjects
NCT ID: NCT01596777
Last Updated: 2016-10-26
Study Results
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Basic Information
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COMPLETED
PHASE1
15 participants
INTERVENTIONAL
2010-01-31
2010-05-31
Brief Summary
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Detailed Description
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Opioid-induced constipation is predominantly mediated by gastrointestinal μ-opioid receptors. Selective blockade of these peripheral receptors might relieve constipation without compromising centrally mediated effects of opioid analgesia or precipitating withdrawal.
Naloxone is a competitive antagonist of opioid receptors inside and outside the central nervous system used as a solution for injection in the treatment of opioid overdose. When administered orally, it can reduce opioid-induced constipation due to a local action in the gut.
Another way to prevent central actions is the use of opioid antagonists which can't penetrate the blood-brain barrier such as methylnaltrexone and alvimopan. Their antagonism of μ-opioid receptors in the gastrointestinal tract seems to reverse opioid-induced gut hypomotility.
It is assumed that methylnaltrexone after oral administration influences intestinal motility by local blockade of opioid receptors along the luminal surface of the gut. Because methylnaltrexone seems to have an absorption window in the proximal small intestine as caused by lower activity of P-glycoprotein in that region (similar to other quaternary compounds, eg. trospium chloride), immediate release (uncoated) methylnaltrexone is better absorbed form the small intestine and might therefore be less active than the enteric-coated drug.
However, the pharmacokinetic and pharmacodynamic data on oral methylnaltrexone are very preliminarily so far. Furthermore, intestinal transit time has been measured using lactulose as a probe compound that has an own laxative effect.
Therefore, the following clinical study was initiated to proof the concept in a controlled clinical trial in healthy subjects, whether methylnaltrexone antagonizes the loperamide induced delay of oro-cecal and whole-gut transit time after oral administration of immediate and extended release capsules in comparison to subcutaneous administration.
Loperamide is an opioid agonist and acts on the µ-receptors in the myenteric plexus. It does not affect the central nervous system like other opioids. Loperamide significantly prolongs the mouth-to-cecum transit time as evaluated by the lactulose hydrogen breath test. This effect may be antagonized by the concomitant administration of naloxone.
Conditions
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Keywords
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Study Design
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RANDOMIZED
CROSSOVER
BASIC_SCIENCE
TRIPLE
Study Groups
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Treatment A
Administration of LOP placebo (-24 h, -12 h, -1 h, 12 h), Colon Transit (-24 h, -12 h, -1 h), SSP (+ 2 h) and MNTX placebo (0 h). To asses the oro-cecal and whole-gut transit time under placebo condition.
Loperamide placebo
200 ml apple juice
Methylnaltrexone placebo
Methylnaltrexone placebo capsule (identical to MNTX IR and MNTX ER)
Colon Transit
3x1 capsules containing radio-opaque marker of 6 different shapes (in two consecutive study periods, capsules with different shapes of the markers are given)
Sulfasalazine
500 mg Azulfidine® (Pharmacia)
Treatment B
Administration of LOP 4 mg (-24 h, -12 h, -1 h, 12 h), Colon Transit (-24 h, -12 h, -1 h), SSP (+ 2 h) and MNTX placebo (0 h). To asses the oro-cecal and whole-gut transit time under loperamide-induced obstipation condition.
Loperamide
20 ml Loperamid-ratiopharm® Lösung (ratiopharm) in 180 ml apple juice prepared before administration
Methylnaltrexone placebo
Methylnaltrexone placebo capsule (identical to MNTX IR and MNTX ER)
Colon Transit
3x1 capsules containing radio-opaque marker of 6 different shapes (in two consecutive study periods, capsules with different shapes of the markers are given)
Sulfasalazine
500 mg Azulfidine® (Pharmacia)
Treatment C
Administration of LOP 4 mg (-24 h, -12 h, -1 h, 12 h), Colon Transit (-24 h, -12 h, -1 h), SSP (+ 2 h) and MNTX 12 mg sc. (0 h). To assess the effects of methylnaltrexone in preventing loperamide-induced delay of the oro-cecal and whole-gut transit time and to measure pharmacokinetics of methylnaltrexone after subcutaneous administration.
Loperamide
20 ml Loperamid-ratiopharm® Lösung (ratiopharm) in 180 ml apple juice prepared before administration
Methylnaltrexone 12 mg sc.
RELISTOR 12 mg/0.6 ml Injektionslösung (Wyeth)
Colon Transit
3x1 capsules containing radio-opaque marker of 6 different shapes (in two consecutive study periods, capsules with different shapes of the markers are given)
Sulfasalazine
500 mg Azulfidine® (Pharmacia)
Treatment D
Administration of LOP 4 mg (-24 h, -12 h, -1 h, 12 h), Colon Transit (-24 h, -12 h, -1 h), SSP (+ 2 h) and MNTX IR (0 h). To assess the effects of methylnaltrexone in preventing loperamide-induced delay of the oro-cecal and whole-gut transit time and to measure pharmacokinetics of methylnaltrexone after oral administration of immediate release capsule.
Loperamide
20 ml Loperamid-ratiopharm® Lösung (ratiopharm) in 180 ml apple juice prepared before administration
Methylnaltrexone IR capsule
Methylnaltrexone bromide 500 mg IR capsule
Colon Transit
3x1 capsules containing radio-opaque marker of 6 different shapes (in two consecutive study periods, capsules with different shapes of the markers are given)
Sulfasalazine
500 mg Azulfidine® (Pharmacia)
Treatment E
Administration of LOP 4 mg (-24 h, -12 h, -1 h, 12 h), Colon Transit (-24 h, -12 h, -1 h), SSP (+ 2 h) and MNTX ER (0 h). To assess the effects of methylnaltrexone in preventing loperamide-induced delay of the oro-cecal and whole-gut transit time and to measure pharmacokinetics of methylnaltrexone after oral administration of extended release capsule.
Loperamide
20 ml Loperamid-ratiopharm® Lösung (ratiopharm) in 180 ml apple juice prepared before administration
Methylnaltrexone ER capsule
Methylnaltrexone bromide 500 mg ER capsule
Colon Transit
3x1 capsules containing radio-opaque marker of 6 different shapes (in two consecutive study periods, capsules with different shapes of the markers are given)
Sulfasalazine
500 mg Azulfidine® (Pharmacia)
Interventions
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Loperamide
20 ml Loperamid-ratiopharm® Lösung (ratiopharm) in 180 ml apple juice prepared before administration
Loperamide placebo
200 ml apple juice
Methylnaltrexone placebo
Methylnaltrexone placebo capsule (identical to MNTX IR and MNTX ER)
Methylnaltrexone 12 mg sc.
RELISTOR 12 mg/0.6 ml Injektionslösung (Wyeth)
Methylnaltrexone IR capsule
Methylnaltrexone bromide 500 mg IR capsule
Methylnaltrexone ER capsule
Methylnaltrexone bromide 500 mg ER capsule
Colon Transit
3x1 capsules containing radio-opaque marker of 6 different shapes (in two consecutive study periods, capsules with different shapes of the markers are given)
Sulfasalazine
500 mg Azulfidine® (Pharmacia)
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* sex: male and female
* ethnic origin: Caucasian
* minimal body weight: 62 kg
* body mass index: ≥ 19 kg/m² and ≤ 27 kg/m²
* good health as evidenced by the results of the clinical examination, ECG, and the laboratory check-up, which were judged by the clinical investigator not to differ in a clinical relevant way from the normal state
* written informed consent
Exclusion Criteria
* gastrointestinal diseases and/or pathological findings, which might interfere with pharmacokinetics and pharmacodynamics of the study medication
* drug or alcohol dependence
* positive drug or alcohol screening
* smokers of 10 or more cigarettes per day
* positive results in HIV, HBV and HCV screenings
* volunteers who were on a diet which could affect the pharmacokinetics of the drug
* heavy tea or coffee drinkers (more than 1 L per day)
* lactation, pregnancy test positive or not performed or women of child-bearing age without safe contraception
* volunteers suspected or known not to follow instructions of the clinical investigators
* volunteers who were unable to understand the written and verbal instructions, in particular regarding the risks and inconveniences they would have been 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
* any medication within 4 weeks prior to the intended first administration of the study medication which might have influenced functions of the gastrointestinal tract (e.g. laxatives, metoclopramide, loperamide, antacids, H2-receptor antagonists, proton pump inhibitors)
* 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
* known allergic reactions to the active ingredients used or to constituents of the study medication
* deficiency of glucose-6-phosphate dehydrogenase
18 Years
45 Years
ALL
Yes
Sponsors
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University Medicine Greifswald
OTHER
Responsible Party
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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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LOP-MNTX-2009
Identifier Type: -
Identifier Source: org_study_id