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.

Study Overview

• Status: Completed
• Conditions: Postmenopausal Osteoporosis
• Intervention / Treatment: Drug: Denosumab; Drug: 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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

General Publications

• 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.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): July 1, 2011
• Study Completion (Actual): July 1, 2011

Study Registration Dates

• First Submitted: October 14, 2010
• First Submitted That Met QC Criteria: October 14, 2010
• First Posted (Estimate): October 15, 2010

Study Record Updates

• Last Update Posted (Actual): August 7, 2018
• Last Update Submitted That Met QC Criteria: July 9, 2018
• Last Verified: September 1, 2015

More Information

Terms related to this study

• Keywords: Phase 1; Osteoporosis; Amgen; Postmenopausal
• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Osteoporosis; Osteoporosis, Postmenopausal; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Bone Density Conservation Agents; Midazolam; Denosumab
• Other Study ID Numbers: 20101131