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

Phase 1

Completed

Conditions: Postmenopausal Osteoporosis

Interventions: Drug: Midazolam
Drug: Denosumab

Registration Number: NCT01221727

Lead Sponsor: Amgen

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 30

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Denosumab	Midazolam	Eighteen (18) subjects will receive denosumab.
Midazolam	Denosumab	All 27 subjects will receive midazolam.

Primary Outcome Measures

Name	Time	Method
Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam With Denosumab Group	From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose	AUC Subject denotes the inter-subject variability, while AUC Residual denotes the intra-subject variability
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)	From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose	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 PK Maximum Observed Plasma Concentration (Cmax) Parameter for Midazolam With Denosumab Group	From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose	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)	From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose	The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.

Secondary Outcome Measures

Name	Time	Method
Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only)	From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose	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	From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose	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	From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose	Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability.
Summary of Serum C-Telopeptide Concentration	Baseline (day 2 pre-dose) to day 16	This table summarizes serum C-Telopeptide (sCTX) concentration raw values for Midazolam with Denosumab group.
Ratio of PK AUC Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only)	From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose	The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.
Summary of Serum Denosumab Concentration	Baseline (day 2 pre-dose) to day 16	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 Percent Change From Baseline to Day 16 for Serum C-Telopeptide Concentration	Baseline (day 2 pre-dose) to day 16	This table summarizes percent change from baseline to day 16 for serum C-Telopeptide (sCTX) concentration raw values for Midazolam with Denosumab group.