Clinical trial NCT01221727: The Effects of Denosumab on the Pharmacokinetics (PK) of Midazolam
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Postmenopausal Osteoporosis
Keywords: Amgen
Phase 1
Postmenopausal
Osteoporosis
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2010-10-15
Enrollment: 30
Sex: FEMALE
Minimum age (years): 45
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: 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)
timeFrame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
measure: Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam With Denosumab Group
timeFrame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
measure: Estimates of Inter- and Intra-subject Variability for PK Maximum Observed Plasma Concentration (Cmax) Parameter for Midazolam With Denosumab Group
timeFrame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
measure: Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only)
timeFrame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Secondary outcomes:
measure: Ratio of PK AUC Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only)
timeFrame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
measure: Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam Only Group
timeFrame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
measure: Estimates of Inter- and Intra-subject Variability for PK Cmax Parameter for Midazolam Only Group
timeFrame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
measure: Summary of Serum Denosumab Concentration
timeFrame: Baseline (day 2 pre-dose) to day 16
measure: Summary of Serum C-Telopeptide Concentration
timeFrame: Baseline (day 2 pre-dose) to day 16
measure: Summary of Percent Change From Baseline to Day 16 for Serum C-Telopeptide Concentration
timeFrame: Baseline (day 2 pre-dose) to day 16
measure: Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only)
timeFrame: From day 1 pre-dose to 24 hours post-dose and from day 16 pre-dose to 24 hours post-dose
Other outcomes:
Locations:
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: 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.