The Effects of Denosumab on the Pharmacokinetics (PK) of Midazolam

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Amgen
ClinicalTrials.gov Identifier:
NCT01221727
First received: October 14, 2010
Last updated: July 18, 2014
Last verified: July 2014
  Purpose

This is a multi-center, open-label, drug-drug interaction study in postmenopausal women with osteoporosis.


Condition Intervention Phase
Postmenopausal Osteoporosis
Drug: Denosumab
Drug: Midazolam
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: The Effects of Denosumab on the Pharmacokinetics (PK) of Midazolam, a Cytochrome P450 3A4/P-gp (CYP3A4) Substrate, in Postmenopausal Osteoporotic Women

Resource links provided by NLM:


Further study details as provided by Amgen:

Primary Outcome Measures:
  • Ratio of Pharmcokinetic (PK) Area Under the Concentration Time Curve (AUC) Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only) [ Time Frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose ] [ Designated as safety issue: No ]
    The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.

  • Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam With Denosumab Group [ Time Frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose ] [ Designated as safety issue: No ]
    AUC Subject denotes the inter-subject variability, while AUC Residual denotes the intra-subject variability

  • Estimates of Inter- and Intra-subject Variability for PK Maximum Observed Plasma Concentration (Cmax) Parameter for Midazolam With Denosumab Group [ Time Frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose ] [ Designated as safety issue: No ]
    Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability

  • Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only) [ Time Frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose ] [ Designated as safety issue: No ]
    The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.


Secondary Outcome Measures:
  • Ratio of PK AUC Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only) [ Time Frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose ] [ Designated as safety issue: No ]
    The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.

  • Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam Only Group [ Time Frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose ] [ Designated as safety issue: No ]
    AUC Subject denotes the inter-subject variability, while AUC Residual denotes the intra-subject variability.

  • Estimates of Inter- and Intra-subject Variability for PK Cmax Parameter for Midazolam Only Group [ Time Frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose ] [ Designated as safety issue: No ]
    Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability.

  • Summary of Serum Denosumab Concentration [ Time Frame: Baseline (day 2 pre-dose) to day 16 ] [ Designated as safety issue: No ]
    This table summarizes serum Denosumab for Midazolam with Denosumab group. The Lower Limit Of Quantification (LLOQ) is 20 ng/mL. On Day 2 (pre-dose), the true value is below LLOQ, and is treated as 0 in the analysis.

  • Summary of Serum C-Telopeptide Concentration [ Time Frame: Baseline (day 2 pre-dose) to day 16 ] [ Designated as safety issue: No ]
    This table summarizes serum C-Telopeptide (sCTX) concentration raw values for Midazolam with Denosumab group.

  • Summary of Percent Change From Baseline to Day 16 for Serum C-Telopeptide Concentration [ Time Frame: Baseline (day 2 pre-dose) to day 16 ] [ Designated as safety issue: No ]
    This table summarizes percent change from baseline to day 16 for serum C-Telopeptide (sCTX) concentration raw values for Midazolam with Denosumab group.

  • Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only) [ Time Frame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose ] [ Designated as safety issue: No ]
    The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.


Enrollment: 30
Study Start Date: November 2010
Study Completion Date: July 2011
Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Midazolam
All 27 subjects will receive midazolam.
Drug: Denosumab
Eighteen (18) subjects will receive 1 fixed dose administration of denosumab.
Other Name: AMG 162
Active Comparator: Denosumab
Eighteen (18) subjects will receive denosumab.
Drug: Midazolam
All subjects will receive two oral dose administrations of midazolam.

Detailed Description:

Approximately 27 subjects (Group A: 18; Group B: 9) will receive a 2 mg oral dose of midazolam on day 1 followed by a 24 hour PK collection. Subjects randomized to Group A will receive a single 60 mg subcutaneous (SC) dose of denosumab on day 2 administered in the abdomen. On study day 16, another 2 mg oral dose of midazolam will be administered to all subjects (Groups A and B) followed by a 24 hour PK collection. The primary analysis to determine the effect of denosumab on the PK of midazolam will be based on data from subjects in Group A only.

  Eligibility

Ages Eligible for Study:   45 Years to 75 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Between 45 to 75 years of age
  • Postmenopausal women
  • Osteoporosis

Exclusion Criteria:

  • Use of any known inhibitors of cytochrome P450 3A4/P-gp (CYP3A4) within 14 days or 5 half lives, whichever is longer; or grapefruit juice or grapefruit containing products within 7 days prior to investigational product administration
  • Use of any known CYP3A4 inducers within 30 days or 5 half-lives, whichever is longer, prior to investigational product administration
  • Use of any herbal medicine with a known impact on CYP3A4 (eg, St. John's wort) within 30 days prior to investigational product administration
  • Current use of medications prescribed for osteoporosis treatment
  • Use of midazolam within 14 days prior to investigational product administration
  • Influenza or other vaccination within 28 days of screening
  • Previous exposure to denosumab
  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: NCT01221727

Sponsors and Collaborators
Amgen
Investigators
Study Director: MD Amgen
  More Information

Additional Information:
No publications provided

Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT01221727     History of Changes
Other Study ID Numbers: 20101131
Study First Received: October 14, 2010
Results First Received: February 13, 2013
Last Updated: July 18, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Amgen:
Amgen
Phase 1
Postmenopausal
Osteoporosis

Additional relevant MeSH terms:
Osteoporosis
Osteoporosis, Postmenopausal
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Midazolam
Adjuvants, Anesthesia
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Anti-Anxiety Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Psychotropic Drugs
Hypnotics and Sedatives
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 29, 2014