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

• ClinicalTrials.gov Identifier: NCT01221727
• Recruitment Status: Completed
• First Posted: October 15, 2010
• Results First Posted: November 7, 2013
• Last Update Posted: August 7, 2018
• Sponsor: Amgen
• Information provided by (Responsible Party): Amgen

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Postmenopausal Osteoporosis	Drug: Denosumab; Drug: Midazolam	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: November 2010
• Actual Primary Completion Date: July 2011
• Actual Study Completion Date: July 2011

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. 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 ]
   The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.
2. 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 ]
   AUC Subject denotes the inter-subject variability, while AUC Residual denotes the intra-subject variability
3. 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 ]
   Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability
4. 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 ]
   The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.

Secondary Outcome Measures :

1. 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 ]
   The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.
2. 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 ]
   AUC Subject denotes the inter-subject variability, while AUC Residual denotes the intra-subject variability.
3. 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 ]
   Cmax Subject denotes the inter-subject variability, while Cmax Residual denotes the intra-subject variability.
4. Summary of Serum Denosumab Concentration [ Time Frame: 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.
5. Summary of Serum C-Telopeptide Concentration [ Time Frame: Baseline (day 2 pre-dose) to day 16 ]
   This table summarizes serum C-Telopeptide (sCTX) concentration raw values for Midazolam with Denosumab group.
6. Summary of Percent Change From Baseline to Day 16 for Serum C-Telopeptide Concentration [ Time Frame: 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.
7. 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 ]
   The ratio and confidence interval are calculated based on natural log scale data and converted back to the original scale.

Eligibility Criteria

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

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

Contacts and Locations

Sponsors and Collaborators

Amgen

Investigators

• Study Director: MD; Amgen

More Information

Additional Information:

AmgenTrials clinical trials website 

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.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT01221727
• Other Study ID Numbers: 20101131
• First Posted: October 15, 2010
• Results First Posted: November 7, 2013
• Last Update Posted: August 7, 2018
• Last Verified: September 2015

Keywords provided by Amgen:

Amgen; Phase 1; Postmenopausal; Osteoporosis

Additional relevant MeSH terms:

Osteoporosis; Osteoporosis, Postmenopausal; Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Denosumab; Midazolam; Adjuvants, Anesthesia; Hypnotics and Sedatives; Central Nervous System Depressants; Physiological Effects of Drugs; Anti-Anxiety Agents; Tranquilizing Agents; Psychotropic Drugs; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; GABA Modulators; GABA Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Bone Density Conservation Agents