Effects of Methylnaltrexone in Comparison to Naloxone on Loperamide-induced Delay of the Oro-cecal, Whole-gut and Colon Transit Time.

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
University Medicine Greifswald
ClinicalTrials.gov Identifier:
NCT01596764
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 repeated-dose methylnaltrexone in preventing loperamide-induced delay of whole-gut, oro-cecal and colon transit time and to measure pharmacokinetics of methylnaltrexone and naloxone-3-glucuronide after oral administration of methylnaltrexone and naloxone.


Condition Intervention Phase
Intestinal Obstruction
Drug: Loperamide placebo
Drug: Loperamide
Device: Colon Transit
Drug: Sulfasalazine
Drug: Placebo of MNTX and NLX
Drug: Naloxone
Drug: Methylnaltrexone
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 Extended Release Methylnaltrexone Bromide (150 mg b.i.d.) in Comparison to Extended Release Naloxone Hydrochloride (20 mg b.i.d.) on Loperamide-induced Delay of the Oro-cecal, Whole-gut and Colon Transit Time in Healthy Subjects.

Resource links provided by NLM:


Further study details as provided by University Medicine Greifswald:

Primary Outcome Measures:
  • Whole-gut transit time (WGT) [ Time Frame: up to 7 days after administration of the study medication ] [ Designated as safety issue: No ]
    Whole-gut transit time (WGT) was assessed by counting the radio-opaque markers with different shapes (Colon Transit) at different time pints in the feces.

  • renal clearance (CLR) [ Time Frame: Blood sampling at 48, 49, 50, 50.5, 51, 51.5, 52, 52.5, 53, 53.5, 54, 54.5, 55, 55.5, 56, 57, 58, 60, 62, 64 h and urine sampling 48-60 h after administration of study medication ] [ Designated as safety issue: No ]
  • area under the curve of administration window (AUC0-12h) [ Time Frame: 48, 49, 50, 50.5, 51, 51.5, 52, 52.5, 53, 53.5, 54, 54.5, 55, 55.5, 56, 57, 58, 60, 62, 64 h after administration of study medication ] [ Designated as safety issue: No ]
  • maximum concentration at steady state (Css max) [ Time Frame: 48, 49, 50, 50.5, 51, 51.5, 52, 52.5, 53, 53.5, 54, 54.5, 55, 55.5, 56, 57, 58, 60, 62, 64 h after administration of study medication ] [ Designated as safety issue: No ]
  • minimum concentration at steady state (Css min) [ Time Frame: 48, 49, 50, 50.5, 51, 51.5, 52, 52.5, 53, 53.5, 54, 54.5, 55, 55.5, 56, 57, 58, 60, 62, 64 h after administration of study medication ] [ Designated as safety issue: No ]
  • average concentration of administration interval (Cav) [ Time Frame: 48, 49, 50, 50.5, 51, 51.5, 52, 52.5, 53, 53.5, 54, 54.5, 55, 55.5, 56, 57, 58, 60, 62, 64 h after administration of study medication ] [ Designated as safety issue: No ]
  • time of maximum concentration (Tmax) [ Time Frame: 48, 49, 50, 50.5, 51, 51.5, 52, 52.5, 53, 53.5, 54, 54.5, 55, 55.5, 56, 57, 58, 60, 62, 64 h after administration of study medication ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Oro-cecal transit time (OCT) [ Time Frame: 48, 49, 50, 50.5, 51, 51.5, 52, 52.5, 53, 53.5, 54, 54.5, 55, 55.5, 56, 57, 58, 60, 62, 64 h after first administration of study medication ] [ Designated as safety issue: No ]
    Oro-cecal transit time (OCT) was defined as the first appearance of sulfapyridine in the plasma (cut of >100 ng/ml) after oral administration of 500 mg sulfasalazine immediate release tablets.

  • Colon transit time (CTT) [ Time Frame: up to 7 days after administration of the study medication ] [ Designated as safety issue: No ]
    Colon transit time (CTT) was derived as the difference WGT minus OCT.


Enrollment: 16
Study Start Date: May 2011
Study Completion Date: January 2012
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Treatment A
Administration of LOP Placebo (0 h, 12 h, 24 h, 36 h, 48 h), Colon Transit (0 h, 12 h, 24 h, 36 h, 48 h), Placebo (0 h, 12 h, 24 h, 36 h, 48 h) and SSP (48 h). To assess WGT, OCT and CTT under placebo condition.
Drug: Loperamide placebo
200 ml apple juice
Other Name: LOP Placebo
Device: Colon Transit
5 capsules containing radio-opaque markers of different shapes, respectively
Drug: Sulfasalazine
Azulfidine® Tabletten 500 mg (Pharmacia/Pfizer) containing 500 mg immediate release sulfasalazine
Other Name: SSP
Drug: Placebo of MNTX and NLX
Placebo capsule (hard gelatine capsule containing multiple sugar spheres)
Other Name: Placebo
Placebo Comparator: Treatment B
Administration of LOP (0 h, 12 h, 24 h, 36 h, 48 h), Colon Transit (0 h, 12 h, 24 h, 36 h, 48 h), Placebo (0 h, 12 h, 24 h, 36 h, 48 h) and SSP (48 h). To assess WGT, OCT and CTT under loperamide-induced obstipation condition.
Drug: Loperamide
20 ml Loperamid-ratiopharm® Lösung (ratiopharm) in 180 ml apple juice containing 4 mg of loperamide hydrochloride (prepared before administration)
Other Name: LOP
Device: Colon Transit
5 capsules containing radio-opaque markers of different shapes, respectively
Drug: Sulfasalazine
Azulfidine® Tabletten 500 mg (Pharmacia/Pfizer) containing 500 mg immediate release sulfasalazine
Other Name: SSP
Drug: Placebo of MNTX and NLX
Placebo capsule (hard gelatine capsule containing multiple sugar spheres)
Other Name: Placebo
Active Comparator: Treatment C
Administration of LOP (0 h, 12 h, 24 h, 36 h, 48 h), Colon Transit (0 h, 12 h, 24 h, 36 h, 48 h), NLX-ER (0 h, 12 h, 24 h, 36 h, 48 h) and SSP (48 h). To describe the effects of repeated-dose naloxone in preventing loperamide-induced delay of WGT, OCT and CTT and measure pharmacokinetics of naloxone.
Drug: Loperamide
20 ml Loperamid-ratiopharm® Lösung (ratiopharm) in 180 ml apple juice containing 4 mg of loperamide hydrochloride (prepared before administration)
Other Name: LOP
Device: Colon Transit
5 capsules containing radio-opaque markers of different shapes, respectively
Drug: Sulfasalazine
Azulfidine® Tabletten 500 mg (Pharmacia/Pfizer) containing 500 mg immediate release sulfasalazine
Other Name: SSP
Drug: Naloxone
Naloxone hydrochloride 20 mg Extended Release Capsule equivalent to 18 mg naloxone (hard gelatine capsule containing a single NLX-ER tablet and multiple sugar spheres)
Other Name: NLX-ER
Active Comparator: Treatment D
Administration of LOP (0 h, 12 h, 24 h, 36 h, 48 h), Colon Transit (0 h, 12 h, 24 h, 36 h, 48 h), MNTX-ER (0 h, 12 h, 24 h, 36 h, 48 h) and SSP (48 h). To describe the effects of repeated-dose methylnaltrexone in preventing loperamide-induced delay of WGT, OCT and CTT and measure pharmacokinetics of methylnaltrexone.
Drug: Loperamide
20 ml Loperamid-ratiopharm® Lösung (ratiopharm) in 180 ml apple juice containing 4 mg of loperamide hydrochloride (prepared before administration)
Other Name: LOP
Device: Colon Transit
5 capsules containing radio-opaque markers of different shapes, respectively
Drug: Sulfasalazine
Azulfidine® Tabletten 500 mg (Pharmacia/Pfizer) containing 500 mg immediate release sulfasalazine
Other Name: SSP
Drug: Methylnaltrexone
Methylnaltrexone bromide 150 mg extended release capsule equivalent to 122 mg methylnaltrexone (hard gelatine capsule containing multiple MNTX-ER micro tablets)
Other Name: MNTX-ER

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. It has a high first-pass metabolism, which is an advantage as the laxative effect can be achieved due to the local action in the gut without significant antagonism of the narcotic analgesic effect of opioid. In some patients, however, withdrawal symptoms or reduction of analgesia was seen.

Another way to prevent central actions is the use of opioid antagonists which cannot 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. The data were obtained in rather small groups with inadequate study design (no randomization, no cross-over, lack of sensitive analytical assays etc.) 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 extended release methylnaltrexone antagonizes the loperamide induced delay of oro-cecal and whole-gut transit time in comparison to extended release naloxone.

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 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
  • volunteers suspected or known not to follow instructions of the clinical investigators
  • 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
  • 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 influence 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-life 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01596764

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: NCT01596764     History of Changes
Other Study ID Numbers: LOP-MNTX-2011
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:
whole-gut transit time
oro-cecal transit time
colon transit time
loperamide-induced obstipation
pharmacokinetics
Methylnaltrexone
Naloxone

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

ClinicalTrials.gov processed this record on April 22, 2014