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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 (LOP-MNTX-2009)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
University Medicine Greifswald
ClinicalTrials.gov Identifier:
NCT01596777
First received: May 7, 2012
Last updated: May 9, 2012
Last verified: May 2012
  Purpose

The purpose of this study is to describe the effects of methylnaltrexone in preventing loperamide-induced delay of the oro-cecal and whole-gut transit time and measure pharmacokinetics of methylnaltrexone after subcutaneous and oral administration of immediate release and extended release capsules.


Condition Intervention Phase
Intestinal Obstruction
Drug: Loperamide
Drug: Loperamide placebo
Drug: Methylnaltrexone placebo
Drug: Methylnaltrexone 12 mg sc.
Drug: Methylnaltrexone IR capsule
Drug: Methylnaltrexone ER capsule
Device: Colon Transit
Drug: Sulfasalazine
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Basic Science
Official Title: 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

Resource links provided by NLM:


Further study details as provided by University Medicine Greifswald:

Primary Outcome Measures:
  • Oro-cecal transit time [ Time Frame: up to 24 h after administration of sulfasalazine ] [ Designated as safety issue: No ]
    Oro-cecal transit time (OCT) was defined as the first appearance of sulfapyridine in the blood after oral administration of 500 mg sulfasalazine immediate release tablets. Because of the high sensitivity of the analytical assay, the OCT was defined as the average of the times needed after sulfasalazine administration to exceed serum concentrations (cut-off) of 50 ng/ml (t50) and of 100 ng/ml (t100).

  • Average whole-gut transit time [ Time Frame: up to 6 days after administration of methylnaltrexone ] [ Designated as safety issue: No ]
    Whole-gut transit time (WGT) was assessed by counting the appearance of radio-opaque markers of different shapes (Colon transit capsules) to diffenrent time pints in the stool, which were administered 24 h, 12 h and 1 h before administration of the methylnaltrexone study medication. The radio-opaque markers in the stool inside the sampling containers were visualized with an X-ray device (Philips Optimus, Philips Healthcare, Hamburg, Germany, CE 257303004) The images were stored and evaluated using the Agfa PACS Workstation, Impact-Version 5.2 (Agfa-Healthcare, Cologne, Germany).

  • renal clearances (CLR) [ Time Frame: blood sampling at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 12, 16, 24 h and urine sampling in 24 hours interval for 3 days after administration of methylnaltrexone ] [ Designated as safety issue: No ]
  • area under the concentrations-time curve (AUC) [ Time Frame: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 12, 16, 24 h after administration of methylnaltrexone ] [ Designated as safety issue: No ]
  • maximum concentration (Cmax) [ Time Frame: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 12, 16, 24 h after administration of methylnaltrexone ] [ Designated as safety issue: No ]
  • time of maximum concentration (Tmax) [ Time Frame: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 12, 16, 24 h after administration of methylnaltrexone ] [ Designated as safety issue: No ]
  • terminal half-life (t1/2) [ Time Frame: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 12, 16, 24 h after administration of methylnaltrexone ] [ Designated as safety issue: No ]
  • mean residence time (MRT) [ Time Frame: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 12, 16, 24 h after administration of methylnaltrexone ] [ Designated as safety issue: No ]
  • distribution volume at steady-state (Vss) [ Time Frame: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 12, 16, 24 h after administration of methylnaltrexone ] [ Designated as safety issue: No ]
  • total body clearance (CLtot) [ Time Frame: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 12, 16, 24 h after administration of methylnaltrexone ] [ Designated as safety issue: No ]
  • bioavailability (F) [ Time Frame: 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 9, 10, 12, 16, 24 h after administration of methylnaltrexone ] [ Designated as safety issue: No ]

Enrollment: 15
Study Start Date: January 2010
Study Completion Date: May 2010
Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: 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.
Drug: Loperamide placebo
200 ml apple juice
Other Name: LOP placebo
Drug: Methylnaltrexone placebo
Methylnaltrexone placebo capsule (identical to MNTX IR and MNTX ER)
Other Name: MNTX placebo
Device: 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)
Drug: Sulfasalazine
500 mg Azulfidine® (Pharmacia)
Other Name: SSP
Placebo Comparator: Treatment B
Administation 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 opstipation condition.
Drug: Loperamide
20 ml Loperamid-ratiopharm® Lösung (ratiopharm) in 180 ml apple juice prepared before administration
Other Name: LOP 4 mg
Drug: Methylnaltrexone placebo
Methylnaltrexone placebo capsule (identical to MNTX IR and MNTX ER)
Other Name: MNTX placebo
Device: 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)
Drug: Sulfasalazine
500 mg Azulfidine® (Pharmacia)
Other Name: SSP
Active Comparator: 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.
Drug: Loperamide
20 ml Loperamid-ratiopharm® Lösung (ratiopharm) in 180 ml apple juice prepared before administration
Other Name: LOP 4 mg
Drug: Methylnaltrexone 12 mg sc.
RELISTOR 12 mg/0.6 ml Injektionslösung (Wyeth)
Other Name: MNTX 12 mg sc.
Device: 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)
Drug: Sulfasalazine
500 mg Azulfidine® (Pharmacia)
Other Name: SSP
Active Comparator: 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.
Drug: Loperamide
20 ml Loperamid-ratiopharm® Lösung (ratiopharm) in 180 ml apple juice prepared before administration
Other Name: LOP 4 mg
Drug: Methylnaltrexone IR capsule
Methylnaltrexone bromide 500 mg IR capsule
Other Name: MNTX IR
Device: 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)
Drug: Sulfasalazine
500 mg Azulfidine® (Pharmacia)
Other Name: SSP
Active Comparator: 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.
Drug: Loperamide
20 ml Loperamid-ratiopharm® Lösung (ratiopharm) in 180 ml apple juice prepared before administration
Other Name: LOP 4 mg
Drug: Methylnaltrexone ER capsule
Methylnaltrexone bromide 500 mg ER capsule
Other Name: MNTX ER
Device: 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)
Drug: Sulfasalazine
500 mg Azulfidine® (Pharmacia)
Other Name: SSP

Detailed Description:

The increasing prevalence of opioid use and consequently, opioid-induced bowel dysfunction has prompted interest in identifying effective treatment options. Until now, the treatment of opioid-induced constipation (OIC) has been viewed as an extension of constipation in general. Traditional therapies for constipation such as bulking agents, stool softeners, stimulant laxatives, and osmotic agents are commonly utilized, but the effects of such therapies are nonspecific and are often generating diarrhea or cramps and some of these drugs cause severe side effects. Furthermore, these conventional measures are sometimes insufficient in some patients, especially those requiring increasing doses of opioids.

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 quatenary 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.

  Eligibility

Ages Eligible for Study:   18 Years to 45 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • age: 18 - 45 years
  • 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:

  • hepatic and renal diseases and/or pathological findings, which might interfere with pharmacokinetics and pharmacodynamics of the study medication
  • 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 1L 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-phospatdehydrogenase
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01596777

Locations
Germany
Department of Clinical Pharmacology, Ernst-Moritz-Arndt-University Greifswald
Greifswald, Mecklenburg-Vorpommern, Germany
Sponsors and Collaborators
University Medicine Greifswald
  More Information

No publications provided

Responsible Party: University Medicine Greifswald
ClinicalTrials.gov Identifier: NCT01596777     History of Changes
Other Study ID Numbers: LOP-MNTX-2009
Study First Received: May 7, 2012
Last Updated: May 9, 2012
Health Authority: Germany: Federal Institute for Drugs and Medical Devices
Germany: Ethics Commission

Keywords provided by University Medicine Greifswald:
Loperamide-induced obstipation
Methylnaltrexone
oro-cecal transit time
whole gut transit time
Pharmacokinetics

Additional relevant MeSH terms:
Intestinal Obstruction
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Antidiarrheals
Loperamide
Methylnaltrexone
Naltrexone
Sulfasalazine
Analgesics
Analgesics, Non-Narcotic
Anti-Infective Agents
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Antirheumatic Agents
Central Nervous System Agents
Gastrointestinal Agents
Narcotic Antagonists
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sensory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on November 27, 2014