A Study to Assess the Effect of Cefiderocol on the Pharmacokinetics (PK) of Midazolam in Healthy Participants

NCT05395104 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 2136R2118
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to determine the effect of repeated doses of cefiderocol on the PK of midazolam.

Conditions

Healthy Volunteers

Outcome Measures

Primary Outcomes (9)

• Maximum Observed Plasma Concentration (Cmax) of Midazolam

  This outcome measure presents the effects of repeated doses of cefiderocol on the pharmacokinetics of midazolam. Cmax is reported as nanograms/milliliter (ng/mL). Day -1 is defined as Baseline.

  0 (predose) up to 24 hours postdose on Day -1 (Midazolam alone at Baseline) and Day 15

• Time to Maximum Plasma Concentration (Tmax) of Midazolam

  This outcome measure presents the effects of repeated doses of cefiderocol on the pharmacokinetics of midazolam. Tmax is reported in hours (hrs). Day -1 is defined as Baseline.

  0 (predose) up to 24 hours postdose on Day -1 (Midazolam alone at Baseline) and Day 15

• Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Midazolam

  This outcome measure presents the effects of repeated doses of cefiderocol on the pharmacokinetics of midazolam. AUC0-last was calculated using the linear up/log down trapezoidal method and is reported as nanograms times hours/milliliter (ng\*hrs/mL). Day -1 is defined as Baseline.

  0 (predose) up to 24 hours postdose on Day -1 (Midazolam alone at Baseline) and Day 15

• Area Under the Concentration-time Curve Extrapolated From Time 0 to Infinity (AUC0-inf) of Midazolam

  This outcome measure presents the effects of repeated doses of cefiderocol on the pharmacokinetics of midazolam. AUC0-inf was calculated as: AUC0-last + \[Clast/λz\], where Clast is the last measured concentration and λz is the plasma terminal elimination rate constant on Days -1 and 15. Day -1 is defined as Baseline.

  0 (predose) up to 24 hours postdose on Day -1 (Midazolam alone at Baseline) and Day 15

• Terminal Elimination Half-life (t1/2,z) of Midazolam

  This outcome measure presents the effects of repeated doses of cefiderocol on the pharmacokinetics of midazolam. t1/2,z was calculated as: (ln2)/λz on Days -1 and 15. Day -1 is defined as Baseline.

  0 (predose) up to 24 hours postdose on Day -1 (Midazolam alone at Baseline) and Day 15

• Terminal Elimination Rate Constant (λz) of Midazolam

  This outcome measure presents the effects of repeated doses of cefiderocol on the pharmacokinetics of midazolam. λz is the magnitude of the slope of the linear regression of the log concentration versus time profile during the terminal phase on Days -1 and 15 and is reported as 1/hours (1/h). Day -1 is defined as Baseline.

  0 (predose) up to 24 hours postdose on Day -1 (Midazolam alone at Baseline) and Day 15

• Mean Residence Time (MRT) of Midazolam

  This outcome measure presents the effects of repeated doses of cefiderocol on the pharmacokinetics of midazolam. MRT was calculated as: AUMC0-inf/AUC0-inf, and AUMC0-inf is the area under the first moment curve extrapolated to infinity on Days -1 and 15. Day -1 is defined as Baseline.

  0 (predose) up to 24 hours postdose on Day -1 (Midazolam alone at Baseline) and Day 15

• Apparent Total Clearance (CL/F) of Midazolam

  This outcome measure presents the effects of repeated doses of cefiderocol on the pharmacokinetics of midazolam. CL/F was calculated as: Dose/AUC0-inf on Days -1 and 15 and is reported as liters/hr. Day -1 is defined as Baseline.

  0 (predose) up to 24 hours postdose on Day -1 (Midazolam alone at Baseline) and Day 15

• Apparent Volume of Distribution (Vz/F) of Midazolam

  This outcome measure presents the effects of repeated doses of cefiderocol on the pharmacokinetics of midazolam. Vz/F was calculated as: Dose/AUC0-inf/λz on Days -1 and 15 and is reported as liters. Day -1 is defined as Baseline.

  0 (predose) up to 24 hours postdose on Day -1 (Midazolam alone at Baseline) and Day 15

Secondary Outcomes (4)

• Cmax of Cefiderocol

  Day 15

• Tmax of Cefiderocol

  Day 15

• Area Under the Plasma Concentration-time Curve Over the Dosing Interval τ (8 Hours) (AUC0-τ) of Cefiderocol

  Day 15

• CL of Cefiderocol

  Day 15

Study Arms (1)

Cefiderocol Plus Midazolam

EXPERIMENTAL

A total of 2 doses of midazolam and 45 doses of cefiderocol was administered to each participant per specified dosing schedule.

Drug: Midazolam; Drug: Cefiderocol

Interventions

Midazolam DRUG

Syrup for oral administration

Cefiderocol Plus Midazolam

Cefiderocol DRUG

Liquid for intravenous infusion

Cefiderocol Plus Midazolam

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Participants who are overtly healthy as determined by medical evaluation, including medical history, physical examination, clinical laboratory tests, vital sign measurements, and 12-lead electrocardiography at the Screening Visit and upon admission to the clinical research unit (CRU).
• Body weight ≥ 50 kilograms (kg) and body mass index within the range of ≥ 18.5 to ≤ 32.0 kg/meter squared at the Screening Visit.

You may not qualify if:

• History or presence of/significant history of or current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrinological, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data.
• Systolic blood pressure outside the range of 90 to 145 millimeters of mercury (mmHg), diastolic blood pressure outside the range of 50 to 95 mmHg, pulse rate outside the range of 40 to 100 beats per minute, or blood pressure or pulse values considered clinically significant by the investigator at the Screening Visit or upon admission to the CRU. Abnormal values may be retested once.
• Lymphoma, leukemia, or any malignancy within the past 5 years, except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years.
• Breast cancer within the past 10 years.
• Past use of over-the-counter or prescription medication, including herbal medications, traditional Chinese medicines, vitamins, minerals, dietary supplements, and vaccines within 14 days (or 5 terminal half-lives, whichever is longer) prior to admission to the CRU (which will occur on Day -2) or intended use of any of the above throughout the study enrollment.
• Significant blood loss of ≥ 500 milliliters or blood or plasma donation within 56 days prior to the Screening Visit until completion of the study, or from the Screening Period until admission to the CRU through completion of the study.
• History of coronavirus disease 2019 (COVID-19) infection within 14 days prior to the Screening Visit or admission, or close contact with a COVID-19 patient in the days prior to the Screening Visit or admission as reported by the participant and the participant's medical history.
• History of drug or alcohol abuse/addiction.
• Regularly consumes excessive amounts of caffeine, defined as \> 6 servings of coffee, tea, caffeinated soft drinks, or other caffeinated beverages per day (1 serving is approximately equivalent to 120 milligrams of caffeine).
• Used tobacco- or nicotine-containing products (including cigarette, pipe, cigar, chewing tobacco, nicotine patch, or nicotine gum) within 6 months prior to admission to the CRU or refuses to refrain from using tobacco- or nicotine-containing products throughout the study (including Follow-up Period).

Sponsors & Collaborators

• Shionogi: lead

Study Sites (1)

Worldwide Clinical Trials

San Antonio, Texas, 78217, United States

Location

MeSH Terms

Interventions

Midazolam; Cefiderocol

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Cephalosporins; beta-Lactams; Lactams; Amides; Organic Chemicals; Thiazines; Sulfur Compounds

Results Point of Contact

• Title: Shionogi Clinical Trials Administrator Clinical Support Help Line
• Organization: Shionogi

Shionogiclintrials-admin@shionogi.co.jp

1-800-849-9707

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 23, 2022
• First Posted: May 27, 2022
• Study Start: May 24, 2022
• Primary Completion: July 13, 2022
• Study Completion: July 13, 2022
• Last Updated: December 14, 2023
• Results First Posted: December 14, 2023

Record last verified: 2023-03

Locations

US (1)