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

A Phase 1, Open-label, 1-sequence Crossover, Drug-drug Interaction Study to Assess the Effect of Repeated Doses of Cefiderocol on the Pharmacokinetics of Midazolam in Healthy Adult Participants

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05395104

Enrollment

Registered

2022-05-27

Start date

2022-05-24

Completion date

2022-07-13

Last updated

2023-12-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Healthy Volunteers

Brief summary

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

Interventions

DRUGMidazolam

Syrup for oral administration

DRUGCefiderocol

Liquid for intravenous infusion

Study design

Allocation

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 60 Years

Healthy volunteers

Yes

Inclusion criteria

* 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.

Exclusion criteria

* 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).

Design outcomes

Primary

Measure	Time frame	Description
Apparent Volume of Distribution (Vz/F) of Midazolam	0 (predose) up to 24 hours postdose on Day -1 (Midazolam alone at Baseline) and Day 15	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.
Terminal Elimination Half-life (t1/2,z) of Midazolam	0 (predose) up to 24 hours postdose on Day -1 (Midazolam alone at Baseline) and Day 15	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.
Terminal Elimination Rate Constant (λz) of Midazolam	0 (predose) up to 24 hours postdose on Day -1 (Midazolam alone at Baseline) and Day 15	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.
Mean Residence Time (MRT) of Midazolam	0 (predose) up to 24 hours postdose on Day -1 (Midazolam alone at Baseline) and Day 15	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.
Apparent Total Clearance (CL/F) of Midazolam	0 (predose) up to 24 hours postdose on Day -1 (Midazolam alone at Baseline) and Day 15	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.
Maximum Observed Plasma Concentration (Cmax) of Midazolam	0 (predose) up to 24 hours postdose on Day -1 (Midazolam alone at Baseline) and Day 15	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.
Time to Maximum Plasma Concentration (Tmax) of Midazolam	0 (predose) up to 24 hours postdose on Day -1 (Midazolam alone at Baseline) and Day 15	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.
Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Midazolam	0 (predose) up to 24 hours postdose on Day -1 (Midazolam alone at Baseline) and Day 15	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.
Area Under the Concentration-time Curve Extrapolated From Time 0 to Infinity (AUC0-inf) of Midazolam	0 (predose) up to 24 hours postdose on Day -1 (Midazolam alone at Baseline) and Day 15	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.

Secondary

Measure	Time frame	Description
Tmax of Cefiderocol	Day 15	This outcome measure presents the pharmacokinetics of cefiderocol when coadministered with midazolam.
Area Under the Plasma Concentration-time Curve Over the Dosing Interval τ (8 Hours) (AUC0-τ) of Cefiderocol	Day 15	This outcome measure presents the pharmacokinetics of cefiderocol when coadministered with midazolam. AUC0-τ was calculated by the linear up/log down trapezoidal method and is reported as micrograms times hours/milliliter (μg\*hrs/mL).
CL of Cefiderocol	Day 15	This outcome measure presents the PK of cefiderocol when coadministered with midazolam. CL was calculated as: Dose/AUC0-τ on Day 15.
Cmax of Cefiderocol	Day 15	This outcome measure presents the pharmacokinetics of cefiderocol when coadministered with midazolam. Cmax is reported as micrograms/milliliter (μg/mL).

Countries

United States

Participant flow

Participants by arm

Arm	Count
Cefiderocol Plus Midazolam A total of 2 doses (5 mg each) of midazolam and 45 doses (2 g each) of cefiderocol were administered to each participant per specified dosing schedule.	14
Total	14

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Met Liver Stopping Criteria	1
Overall Study	Withdrawal by Subject	1

Baseline characteristics

Characteristic	Cefiderocol Plus Midazolam
Age, Continuous	40.9 Years STANDARD_DEVIATION 14.58
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	9 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	7 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	7 Participants
Sex: Female, Male Female	9 Participants
Sex: Female, Male Male	5 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 14
other Total, other adverse events	11 / 14
serious Total, serious adverse events	0 / 14

Outcome results

Primary

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.