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

NCT01596777 | Completed Phase 1

• 1 other identifier: LOP-MNTX-2009
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Intestinal Obstruction

Keywords

Loperamide-induced obstipation; Methylnaltrexone; oro-cecal transit time; whole gut transit time; Pharmacokinetics

Outcome Measures

Primary Outcomes (11)

• Oro-cecal transit time

  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).

  up to 24 h after administration of sulfasalazine

• Average whole-gut transit time

  Whole-gut transit time (WGT) was assessed by counting the appearance of radio-opaque markers of different shapes (Colon transit capsules) to different 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).

  up to 6 days after administration of methylnaltrexone

• renal clearances (CLR)

  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

• area under the concentrations-time curve (AUC)

  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

• maximum concentration (Cmax)

  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

• time of maximum concentration (Tmax)

  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

• terminal half-life (t1/2)

  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

• mean residence time (MRT)

  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

• distribution volume at steady-state (Vss)

  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

• total body clearance (CLtot)

  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

• relative bioavailability (F)

  Ratio AUC of IR and ER formulation over subcutaneous administration

  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

Study Arms (5)

Treatment A

PLACEBO COMPARATOR

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; Drug: Methylnaltrexone placebo; Device: Colon Transit; Drug: Sulfasalazine

Treatment B

PLACEBO COMPARATOR

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.

Drug: Loperamide; Drug: Methylnaltrexone placebo; Device: Colon Transit; Drug: Sulfasalazine

Treatment C

ACTIVE COMPARATOR

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; Drug: Methylnaltrexone 12 mg sc.; Device: Colon Transit; Drug: Sulfasalazine

Treatment D

ACTIVE COMPARATOR

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; Drug: Methylnaltrexone IR capsule; Device: Colon Transit; Drug: Sulfasalazine

Treatment E

ACTIVE COMPARATOR

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; Drug: Methylnaltrexone ER capsule; Device: Colon Transit; Drug: Sulfasalazine

Interventions

Loperamide DRUG

20 ml Loperamid-ratiopharm® Lösung (ratiopharm) in 180 ml apple juice prepared before administration

Also known as: LOP 4 mg

Treatment B; Treatment C; Treatment D; Treatment E

Loperamide placebo DRUG

200 ml apple juice

Also known as: LOP placebo

Treatment A

Methylnaltrexone placebo DRUG

Methylnaltrexone placebo capsule (identical to MNTX IR and MNTX ER)

Also known as: MNTX placebo

Treatment A; Treatment B

Methylnaltrexone 12 mg sc. DRUG

RELISTOR 12 mg/0.6 ml Injektionslösung (Wyeth)

Also known as: MNTX 12 mg sc.

Treatment C

Methylnaltrexone IR capsule DRUG

Methylnaltrexone bromide 500 mg IR capsule

Also known as: MNTX IR

Treatment D

Methylnaltrexone ER capsule DRUG

Methylnaltrexone bromide 500 mg ER capsule

Also known as: MNTX ER

Treatment E

Colon Transit DEVICE

3x1 capsules containing radio-opaque marker of 6 different shapes (in two consecutive study periods, capsules with different shapes of the markers are given)

Treatment A; Treatment B; Treatment C; Treatment D; Treatment E

Sulfasalazine DRUG

500 mg Azulfidine® (Pharmacia)

Also known as: SSP

Treatment A; Treatment B; Treatment C; Treatment D; Treatment E

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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 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

Sponsors & Collaborators

• University Medicine Greifswald: lead

Study Sites (1)

Department of Clinical Pharmacology, Ernst-Moritz-Arndt-University Greifswald

Greifswald, Mecklenburg-Vorpommern, Germany

Location

MeSH Terms

Conditions

Intestinal Obstruction

Interventions

Loperamide; methylnaltrexone; Sulfasalazine

Condition Hierarchy (Ancestors)

Intestinal Diseases; Gastrointestinal Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 7, 2012
• First Posted: May 11, 2012
• Study Start: January 1, 2010
• Primary Completion: March 1, 2010
• Study Completion: May 1, 2010
• Last Updated: October 26, 2016

Record last verified: 2016-10

Locations

DE (1)