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: September 5, 2013
Last verified: September 2013

October 14, 2010
September 5, 2013
November 2010
July 2011   (final data collection date for primary outcome measure)
  • 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.
The area under the serum concentration-time curve and maximum observed concentration for midazolam from subjects who receive denosumab administration. [ Time Frame: A total of 47 days following investigational product administration. ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01221727 on ClinicalTrials.gov Archive Site
  • 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.
  • Additional midazolam pharmacokinetic (PK) parameters (eg, time of maximum drug concentration, half-life). [ Time Frame: A total of 47 days following investigational product administration. ] [ Designated as safety issue: No ]
  • The serum denosumab and serum C-telopeptide concentrations. [ Time Frame: A total of 47 days following investigational product administration. ] [ Designated as safety issue: No ]
  • The area under the serum concentration-time curve and maximum observed concentration for midazolam from subjects who only receive midazolam administration. [ Time Frame: A total of 47 days following investigational product administration. ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
The Effects of Denosumab on the Pharmacokinetics (PK) of Midazolam
The Effects of Denosumab on the Pharmacokinetics (PK) of Midazolam, a Cytochrome P450 3A4/P-gp (CYP3A4) Substrate, in Postmenopausal Osteoporotic Women

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

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.

Interventional
Phase 1
Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Postmenopausal Osteoporosis
  • Drug: Denosumab
    Eighteen (18) subjects will receive 1 fixed dose administration of denosumab.
    Other Name: AMG 162
  • Drug: Midazolam
    All subjects will receive two oral dose administrations of midazolam.
  • Midazolam
    All 27 subjects will receive midazolam.
    Intervention: Drug: Denosumab
  • Active Comparator: Denosumab
    Eighteen (18) subjects will receive denosumab.
    Intervention: Drug: Midazolam
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
30
July 2011
July 2011   (final data collection date for primary outcome measure)

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
Female
45 Years to 75 Years
No
Contact information is only displayed when the study is recruiting subjects
Not Provided
 
NCT01221727
20101131
No
Amgen
Amgen
Not Provided
Study Director: MD Amgen
Amgen
September 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP