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

Information source: Amgen
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Postmenopausal Osteoporosis

Intervention: Denosumab (Drug); Midazolam (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: Amgen

Official(s) and/or principal investigator(s):
MD, Study Director, Affiliation: Amgen

Summary

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

Clinical Details

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 design: Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

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)

Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam With Denosumab Group

Estimates of Inter- and Intra-subject Variability for PK Maximum Observed Plasma Concentration (Cmax) Parameter for Midazolam With Denosumab Group

Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam With the Presence of Denosumab) and Day 1 (Midazolam Only)

Secondary outcome:

Ratio of PK AUC Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only)

Estimates of Inter- and Intra-subject Variability for the PK AUC Parameters for Midazolam Only Group

Estimates of Inter- and Intra-subject Variability for PK Cmax Parameter for Midazolam Only Group

Summary of Serum Denosumab Concentration

Summary of Serum C-Telopeptide Concentration

Summary of Percent Change From Baseline to Day 16 for Serum C-Telopeptide Concentration

Ratio of PK Cmax Parameter Estimates Between Day 16 (Midazolam Only) and Day 1(Midazolam Only)

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

Minimum age: 45 Years. Maximum age: 75 Years. Gender(s): Female.

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

Locations and Contacts

Additional Information

AmgenTrials clinical trials website

Related 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.

Starting date: November 2010
Last updated: July 18, 2014

Page last updated: August 23, 2015

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