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

Primary Purpose

Postmenopausal Osteoporosis

Status
Completed
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Denosumab
Midazolam
Sponsored by
Amgen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Postmenopausal Osteoporosis focused on measuring Amgen, Phase 1, Postmenopausal, Osteoporosis

Eligibility Criteria

45 Years - 75 Years (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Other

    Active Comparator

    Arm Label

    Midazolam

    Denosumab

    Arm Description

    All 27 subjects will receive midazolam.

    Eighteen (18) subjects will receive denosumab.

    Outcomes

    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)
    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
    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
    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)
    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)
    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
    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
    Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability.
    Summary of Serum Denosumab Concentration
    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
    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
    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)
    The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.

    Full Information

    First Posted
    October 14, 2010
    Last Updated
    July 9, 2018
    Sponsor
    Amgen
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    1. Study Identification

    Unique Protocol Identification Number
    NCT01221727
    Brief Title
    The Effects of Denosumab on the Pharmacokinetics (PK) of Midazolam
    Official Title
    The Effects of Denosumab on the Pharmacokinetics (PK) of Midazolam, a Cytochrome P450 3A4/P-gp (CYP3A4) Substrate, in Postmenopausal Osteoporotic Women
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    September 2015
    Overall Recruitment Status
    Completed
    Study Start Date
    November 2010 (undefined)
    Primary Completion Date
    July 2011 (Actual)
    Study Completion Date
    July 2011 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Amgen

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

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

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Postmenopausal Osteoporosis
    Keywords
    Amgen, Phase 1, Postmenopausal, Osteoporosis

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 1
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    30 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Midazolam
    Arm Type
    Other
    Arm Description
    All 27 subjects will receive midazolam.
    Arm Title
    Denosumab
    Arm Type
    Active Comparator
    Arm Description
    Eighteen (18) subjects will receive denosumab.
    Intervention Type
    Drug
    Intervention Name(s)
    Denosumab
    Other Intervention Name(s)
    AMG 162
    Intervention Description
    Eighteen (18) subjects will receive 1 fixed dose administration of denosumab.
    Intervention Type
    Drug
    Intervention Name(s)
    Midazolam
    Intervention Description
    All subjects will receive two oral dose administrations of midazolam.
    Primary Outcome Measure Information:
    Title
    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)
    Description
    The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.
    Time Frame
    From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
    Title
    Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam With Denosumab Group
    Description
    AUC Subject denotes the inter-subject variability, while AUC Residual denotes the intra-subject variability
    Time Frame
    From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
    Title
    Estimates of Inter- and Intra-subject Variability for PK Maximum Observed Plasma Concentration (Cmax) Parameter for Midazolam With Denosumab Group
    Description
    Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability
    Time Frame
    From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
    Title
    Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only)
    Description
    The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.
    Time Frame
    From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
    Secondary Outcome Measure Information:
    Title
    Ratio of PK AUC Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only)
    Description
    The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.
    Time Frame
    From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
    Title
    Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam Only Group
    Description
    AUC Subject denotes the inter-subject variability, while AUC Residual denotes the intra-subject variability.
    Time Frame
    From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
    Title
    Estimates of Inter- and Intra-subject Variability for PK Cmax Parameter for Midazolam Only Group
    Description
    Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability.
    Time Frame
    From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
    Title
    Summary of Serum Denosumab Concentration
    Description
    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.
    Time Frame
    Baseline (day 2 pre-dose) to day 16
    Title
    Summary of Serum C-Telopeptide Concentration
    Description
    This table summarizes serum C-Telopeptide (sCTX) concentration raw values for Midazolam with Denosumab group.
    Time Frame
    Baseline (day 2 pre-dose) to day 16
    Title
    Summary of Percent Change From Baseline to Day 16 for Serum C-Telopeptide Concentration
    Description
    This table summarizes percent change from baseline to day 16 for serum C-Telopeptide (sCTX) concentration raw values for Midazolam with Denosumab group.
    Time Frame
    Baseline (day 2 pre-dose) to day 16
    Title
    Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only)
    Description
    The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.
    Time Frame
    From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose

    10. Eligibility

    Sex
    Female
    Minimum Age & Unit of Time
    45 Years
    Maximum Age & Unit of Time
    75 Years
    Accepts Healthy Volunteers
    No
    Eligibility 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
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    MD
    Organizational Affiliation
    Amgen
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Citations:
    PubMed Identifier
    25505582
    Citation
    Jang G, Kaufman A, Lee E, Hamilton L, Hutton S, Egbuna O, Padhi D. A clinical therapeutic protein drug-drug interaction study: coadministration of denosumab and midazolam in postmenopausal women with osteoporosis. Pharmacol Res Perspect. 2014 Apr;2(2):e00033. doi: 10.1002/prp2.33. Epub 2014 Mar 13.
    Results Reference
    background
    Links:
    URL
    http://www.amgentrials.com
    Description
    AmgenTrials clinical trials website

    Learn more about this trial

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

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