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

Postmenopausal Osteoporosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01221727
• Other study ID #: 20101131
• Status: Completed
• Phase: Phase 1
• Start date: November 2010
• Est. completion date: July 2011

Study information

• Verified date: September 2015
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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 information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: July 2011
• Est. primary completion date: July 2011
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 45 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Osteoporosis
• Osteoporosis, Postmenopausal
• Postmenopausal Osteoporosis

Intervention

Drug:
• Denosumab
Eighteen (18) subjects will receive 1 fixed dose administration of denosumab.
• Midazolam
All subjects will receive two oral dose administrations of midazolam.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   AmgenTrials clinical trials website