A Bioavailability Study With Alternate Methods of Administration of Naloxegol Tablets, and Solution

NCT02446171 | Completed Phase 1 Results

• 1 other identifier: D3820C00035
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

This clinical study is an open-label, randomized, 4-period, 4-treatment, crossover, single-center, single-dose bioavailability study with alternate methods of administration of crushed naloxegol tablets, 25 mg and of a naloxegol solution formulation, 25 mg, compared to whole naloxegol tablets, 25 mg, in healthy subjects. The main objective of this study is to determine the bioavailability of each of three alternative methods of naloxegol administration compared to whole naloxegol tablets given orally by assessment of the primary pharmacokinetic (PK) parameters of naloxegol

Conditions

Bioavailability; Healthy Subjects

Keywords

naloxegol tablet crushed; naloxegol oral solution; naloxegol whole tablet; relative bioavailability; Phase I; healthy subjects

Outcome Measures

Primary Outcomes (3)

• Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-infinity).

  Area under plasma concentration-time curve from time zero extrapolated to infinity (AUC) is presented below. Blood was collected pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post-dose to determine naloxegol plasma concentrations.

  Pre-dose (0 hours [within 30 minutes prior to administration of the investigational medicinal product (IMP)]) and post-dose at 0.25 (15 minutes), 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours in each treatment period.

• Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUC 0-t).

  Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration is presented below. Blood was collected pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post-dose to determine naloxegol plasma concentrations.

  Pre-dose (0 hours [within 30 minutes prior to IMP administration]) and post-dose at 0.25 (15 minutes), 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours in each treatment period.

• Observed Maximum Plasma Concentration (Cmax).

  Observed maximum plasma concentration (Cmax) is presented below. Blood was collected pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours post-dose to determine naloxegol plasma concentrations.

  Pre-dose (0 hours [within 30 minutes prior to IMP administration]) and post-dose at 0.25 (15 minutes), 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours in each treatment period.

Secondary Outcomes (14)

• Time to Reach Maximum Plasma Concentration (Tmax).

  Pre-dose (0 hours [within 30 minutes prior to IMP administration]) and post-dose at 0.25 (15 minutes), 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours in each treatment period.

• Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz).

  Pre-dose (0 hours [within 30 minutes prior to IMP administration]) and post-dose at 0.25 (15 minutes), 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours in each treatment period.

• Mean Dissolution Time (MDT).

  Pre-dose (0 hours [within 30 minutes prior to IMP administration]) and post-dose at 0.25 (15 minutes), 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours in each treatment period.

• Mean Residence Time (MRT).

  Pre-dose (0 hours [within 30 minutes prior to IMP administration]) and post-dose at 0.25 (15 minutes), 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours in each treatment period.

• Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC (CL/F).

  Pre-dose (0 hours [within 30 minutes prior to IMP administration]) and post-dose at 0.25 (15 minutes), 0.5 (30 minutes), 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48 and 72 hours in each treatment period.

Study Arms (4)

Treatments A-D-B-C sequence

EXPERIMENTAL

Treatment A in Period 1, Treatment D in Period 2, Treatment B in Period 3 and Treatment C in Period 4

Drug: Naloxegol 25 mg tablet, crushed, suspended in water, given orally; Drug: Naloxegol 25mg tablet crushed, suspended in water, given via nasogastric tube; Drug: Naloxegol 25 mg (10 mL oral solution); Drug: Naloxegol 25 mg tablet, given orally

Treatments B-A-C-D sequence

EXPERIMENTAL

Treatment B in Period 1, Treatment A in Period 2, Treatment C in Period 3 and Treatment D in Period 4

Drug: Naloxegol 25 mg tablet, crushed, suspended in water, given orally; Drug: Naloxegol 25mg tablet crushed, suspended in water, given via nasogastric tube; Drug: Naloxegol 25 mg (10 mL oral solution); Drug: Naloxegol 25 mg tablet, given orally

Treatments C-B-D-A sequence

EXPERIMENTAL

Treatment C in Period 1, Treatment B in Period 2, Treatment D in Period 3 and Treatment A in Period 4

Drug: Naloxegol 25 mg tablet, crushed, suspended in water, given orally; Drug: Naloxegol 25mg tablet crushed, suspended in water, given via nasogastric tube; Drug: Naloxegol 25 mg (10 mL oral solution); Drug: Naloxegol 25 mg tablet, given orally

Treatments D-C-A-B sequence

EXPERIMENTAL

Treatment D in Period 1, Treatment C in Period 2, Treatment A in Period 3 and Treatment B in Period 4

Drug: Naloxegol 25 mg tablet, crushed, suspended in water, given orally; Drug: Naloxegol 25mg tablet crushed, suspended in water, given via nasogastric tube; Drug: Naloxegol 25 mg (10 mL oral solution); Drug: Naloxegol 25 mg tablet, given orally

Interventions

Naloxegol 25 mg tablet, crushed, suspended in water, given orally DRUG

naloxegol 25 mg (1 tablet) crushed, suspended in water, given orally

Also known as: Treatment A, (Test product)

Treatments A-D-B-C sequence; Treatments B-A-C-D sequence; Treatments C-B-D-A sequence; Treatments D-C-A-B sequence

Naloxegol 25mg tablet crushed, suspended in water, given via nasogastric tube DRUG

naloxegol 25 mg (1 tablet) crushed, suspended in water, given via nasogastric tube

Also known as: Treatment B, (Test product)

Treatments A-D-B-C sequence; Treatments B-A-C-D sequence; Treatments C-B-D-A sequence; Treatments D-C-A-B sequence

Naloxegol 25 mg (10 mL oral solution) DRUG

naloxegol 25 mg (10 mL oral solution)

Also known as: Treatment C, (Test product)

Treatments A-D-B-C sequence; Treatments B-A-C-D sequence; Treatments C-B-D-A sequence; Treatments D-C-A-B sequence

Naloxegol 25 mg tablet, given orally DRUG

naloxegol 25 mg (1 tablet) whole tablet, given orally

Also known as: Treatment D, (Reference product)

Treatments A-D-B-C sequence; Treatments B-A-C-D sequence; Treatments C-B-D-A sequence; Treatments D-C-A-B sequence

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy male and female subjects aged 18 to 55 years with suitable veins for cannulation or repeated venipuncture.
• Females must have a negative pregnancy test at screening and on admission to the clinical unit, must not be lactating and must be of non childbearing potential, confirmed at screening by fulfilling one of the following criteria:
• Post-menopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH) levels in the post-menopausal range.
• Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy; but not tubal ligation.
• Have a body mass index (BMI) between 18.5 and 29.9 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
• Able to understand, read and speak the German language.

You may not qualify if:

• History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the potential subject at risk because of participation in the study, or influence the results or the potential subject's ability to participate in the study.
• Current smokers or those who have smoked or used nicotine products within the previous 3 months.
• Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP.
• Drugs include known CYP3A4 and/or P-gp inhibitors and inducers, e.g., diltiazem, verapamil, and erythromycin
• \- Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during 2 weeks prior to the first administration of IMP or longer if the medication has a long half-life.
• For females, hormonal replacement therapy is not allowed.
• Subject with a relevant history of a suicide attempt or suicidal behavior. Any recent suicidal ideation within the last 6 months (a level of 4 or 5), or who are at significant risk to commit suicide, as judged by the investigator using the Columbia-Suicide Severity Rating Scale (C-SSRS).
• Applicable to subjects willing to participate in genetic research: Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection or previous bone marrow transplant.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (1)

Research Site

Berlin, Germany

Location

Related Publications (1)

• Bui K, Birmingham B, Diva U, Berger B. An Open-Label, Randomized Bioavailability Study of Alternative Methods of Oral Administration of Naloxegol in Healthy Subjects. Clin Pharmacol Drug Dev. 2017 Jul;6(4):420-427. doi: 10.1002/cpdd.335. Epub 2017 Jan 27.

  PMID: 28127938 BACKGROUND

MeSH Terms

Interventions

naloxegol; Tablets; Excipients; Water; Solutions

Intervention Hierarchy (Ancestors)

Dosage Forms; Pharmaceutical Preparations; Pharmaceutical Vehicles; Pharmaceutic Aids; Specialty Uses of Chemicals; Chemical Actions and Uses; Hydroxides; Alkalies; Inorganic Chemicals; Anions; Ions; Electrolytes; Oxides; Oxygen Compounds

Results Point of Contact

• Title: Ian Wogan
• Organization: AstraZeneca AB

ClinicalTrialTransparency@astrazeneca.com

+1 301 398 0670

Study Officials

• Rainard Fuhr, Dr. med.

  PAREXEL International GmbH, Berlin

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 29, 2015
• First Posted: May 18, 2015
• Study Start: May 1, 2015
• Primary Completion: July 1, 2015
• Study Completion: July 1, 2015
• Last Updated: March 10, 2017
• Results First Posted: June 9, 2016

Record last verified: 2017-01

Locations

DE (1)