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

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

Detailed Description
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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.

Official Title
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The Effects of Denosumab on the Pharmacokinetics (PK) of Midazolam, a Cytochrome P450 3A4/P-gp (CYP3A4) Substrate, in Postmenopausal Osteoporotic Women

Conditions
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Postmenopausal Osteoporosis

Intervention / Treatment
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* Drug: Denosumab
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Midazolam<br>All 27 subjects will receive midazolam. | Drug: Denosumab<br>* Eighteen (18) subjects will receive 1 fixed dose administration of denosumab.<br>* Other names: AMG 162;|
| Active Comparator: Denosumab<br>Eighteen (18) subjects will receive denosumab. | Drug: Midazolam<br>* All subjects will receive two oral dose administrations of midazolam.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | 
| 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 | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | 
| 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 | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | 
| 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. | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | 
| 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. | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | 
| 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. | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | 
| 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. | Baseline (day 2 pre-dose) to day 16 | 
| Summary of Serum C-Telopeptide Concentration | This table summarizes serum C-Telopeptide (sCTX) concentration raw values for Midazolam with Denosumab group. | Baseline (day 2 pre-dose) to day 16 | 
| 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. | Baseline (day 2 pre-dose) to day 16 | 
| 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. | From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amgen, Phase 1, Postmenopausal, Osteoporosis