Trial Outcomes & Findings for A Study to Assess the Effect of Cefiderocol on the Pharmacokinetics (PK) of Midazolam in Healthy Participants (NCT NCT05395104)

NCT ID: NCT05395104

Last Updated: 2023-12-14

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 14 participants
• Primary outcome timeframe: 0 (predose) up to 24 hours postdose on Day -1 (Midazolam alone at Baseline) and Day 15
• Results posted on: 2023-12-14

Participant Flow

Participant milestones

Measure	Cefiderocol Plus Midazolam A total of 2 doses (5 milligrams \[mg\] each) of midazolam and 45 doses (2 grams \[g\] each) of cefiderocol were administered to each participant per specified dosing schedule.
Overall Study STARTED	14
Overall Study Received At Least 1 Dose Of Study Drug	14
Overall Study COMPLETED	12
Overall Study NOT COMPLETED	2

Reasons for withdrawal

Measure	Cefiderocol Plus Midazolam A total of 2 doses (5 milligrams \[mg\] each) of midazolam and 45 doses (2 grams \[g\] each) of cefiderocol were administered to each participant per specified dosing schedule.
Overall Study Met Liver Stopping Criteria	1
Overall Study Withdrawal by Subject	1

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Cefiderocol Plus Midazolam n=14 Participants 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.
Age, Continuous	40.9 Years STANDARD_DEVIATION 14.58 • n=93 Participants
Sex: Female, Male Female	9 Participants n=93 Participants
Sex: Female, Male Male	5 Participants n=93 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=93 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	9 Participants n=93 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants
Race (NIH/OMB) Asian	0 Participants n=93 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants
Race (NIH/OMB) Black or African American	7 Participants n=93 Participants
Race (NIH/OMB) White	7 Participants n=93 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants

PRIMARY outcome

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

Population: Pharmacokinetics Parameter Population: All participants with at least 1 pharmacokinetics parameter estimated appropriately. Participants in the "Midazolam + Cefiderocol" population with available data were analyzed.

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.

Outcome measures

Measure	Cefiderocol Plus Midazolam n=14 Participants 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.
Maximum Observed Plasma Concentration (Cmax) of Midazolam Midazolam Alone	25.3 ng/mL Geometric Coefficient of Variation 45.3
Maximum Observed Plasma Concentration (Cmax) of Midazolam Midazolam + Cefiderocol	28.8 ng/mL Geometric Coefficient of Variation 35.0

PRIMARY outcome

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

Population: Pharmacokinetics Parameter Population: All participants with at least 1 pharmacokinetics parameter estimated appropriately. Participants in the "Midazolam + Cefiderocol" population with available data were analyzed.

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.

Outcome measures

Measure	Cefiderocol Plus Midazolam n=14 Participants 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.
Time to Maximum Plasma Concentration (Tmax) of Midazolam Midazolam Alone	0.51 hrs Interval 0.5 to 1.0
Time to Maximum Plasma Concentration (Tmax) of Midazolam Midazolam + Cefiderocol	0.51 hrs Interval 0.5 to 1.07

PRIMARY outcome

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

Population: Pharmacokinetics Parameter Population: All participants with at least 1 pharmacokinetics parameter estimated appropriately. Participants in the "Midazolam + Cefiderocol" population with available data were analyzed.

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.

Outcome measures

Measure	Cefiderocol Plus Midazolam n=14 Participants 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.
Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Midazolam Midazolam Alone	66.13 ng*hrs/mL Geometric Coefficient of Variation 46.3
Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Midazolam Midazolam + Cefiderocol	77.37 ng*hrs/mL Geometric Coefficient of Variation 44.2

PRIMARY outcome

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

Population: Pharmacokinetics Parameter Population: All participants with at least 1 pharmacokinetics parameter estimated appropriately. Participants in the "Midazolam + Cefiderocol" population with available data were analyzed.

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.

Outcome measures

Measure	Cefiderocol Plus Midazolam n=14 Participants 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.
Area Under the Concentration-time Curve Extrapolated From Time 0 to Infinity (AUC0-inf) of Midazolam Midazolam Alone	68.69 ng*hrs/mL Geometric Coefficient of Variation 47.8
Area Under the Concentration-time Curve Extrapolated From Time 0 to Infinity (AUC0-inf) of Midazolam Midazolam + Cefiderocol	81.07 ng*hrs/mL Geometric Coefficient of Variation 45.6

PRIMARY outcome

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

Population: Pharmacokinetics Parameter Population: All participants with at least 1 pharmacokinetics parameter estimated appropriately. Participants in the "Midazolam + Cefiderocol" population with available data were analyzed.

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.

Outcome measures

Measure	Cefiderocol Plus Midazolam n=14 Participants 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.
Terminal Elimination Half-life (t1/2,z) of Midazolam Midazolam Alone	5.39 hrs Geometric Coefficient of Variation 33.7
Terminal Elimination Half-life (t1/2,z) of Midazolam Midazolam + Cefiderocol	6.10 hrs Geometric Coefficient of Variation 41.7

PRIMARY outcome

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

Population: Pharmacokinetics Parameter Population: All participants with at least 1 pharmacokinetics parameter estimated appropriately. Participants in the "Midazolam + Cefiderocol" population with available data were analyzed.

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.

Outcome measures

Measure	Cefiderocol Plus Midazolam n=14 Participants 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.
Terminal Elimination Rate Constant (λz) of Midazolam Midazolam Alone	0.1287 1/hrs Geometric Coefficient of Variation 33.7
Terminal Elimination Rate Constant (λz) of Midazolam Midazolam + Cefiderocol	0.1135 1/hrs Geometric Coefficient of Variation 41.7

PRIMARY outcome

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

Population: Pharmacokinetics Parameter Population: All participants with at least 1 pharmacokinetics parameter estimated appropriately. Participants in the "Midazolam + Cefiderocol" population with available data were analyzed.

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.

Outcome measures

Measure	Cefiderocol Plus Midazolam n=14 Participants 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.
Mean Residence Time (MRT) of Midazolam Midazolam Alone	4.86 hrs Geometric Coefficient of Variation 26.5
Mean Residence Time (MRT) of Midazolam Midazolam + Cefiderocol	5.51 hrs Geometric Coefficient of Variation 33.4

PRIMARY outcome

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

Population: Pharmacokinetics Parameter Population: All participants with at least 1 pharmacokinetics parameter estimated appropriately. Participants in the "Midazolam + Cefiderocol" population with available data were analyzed.

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.

Outcome measures

Measure	Cefiderocol Plus Midazolam n=14 Participants 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.
Apparent Total Clearance (CL/F) of Midazolam Midazolam Alone	69.3 liters/hr Geometric Coefficient of Variation 60.3
Apparent Total Clearance (CL/F) of Midazolam Midazolam + Cefiderocol	61.7 liters/hr Geometric Coefficient of Variation 45.6

PRIMARY outcome

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

Population: Pharmacokinetics Parameter Population: All participants with at least 1 pharmacokinetics parameter estimated appropriately. Participants in the "Midazolam + Cefiderocol" population with available data were analyzed.

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.

Outcome measures

Measure	Cefiderocol Plus Midazolam n=14 Participants 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.
Apparent Volume of Distribution (Vz/F) of Midazolam Midazolam Alone	538 liters Geometric Coefficient of Variation 38.4
Apparent Volume of Distribution (Vz/F) of Midazolam Midazolam + Cefiderocol	543 liters Geometric Coefficient of Variation 52.2

SECONDARY outcome

Timeframe: Day 15

Population: Pharmacokinetics Parameter Population: All participants with at least 1 pharmacokinetics parameter estimated appropriately. Participants with available data were analyzed.

This outcome measure presents the pharmacokinetics of cefiderocol when coadministered with midazolam. Cmax is reported as micrograms/milliliter (μg/mL).

Outcome measures

Measure	Cefiderocol Plus Midazolam n=11 Participants 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.
Cmax of Cefiderocol	80.5 μg/mL Geometric Coefficient of Variation 21.8

SECONDARY outcome

Timeframe: Day 15

Population: Pharmacokinetics Parameter Population: All participants with at least 1 pharmacokinetics parameter estimated appropriately. Participants with available data were analyzed.

This outcome measure presents the pharmacokinetics of cefiderocol when coadministered with midazolam.

Outcome measures

Measure	Cefiderocol Plus Midazolam n=11 Participants 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.
Tmax of Cefiderocol	2.92 hrs Interval 2.9 to 2.98

SECONDARY outcome

Timeframe: Day 15

Population: Pharmacokinetics Parameter Population: All participants with at least 1 pharmacokinetics parameter estimated appropriately. Participants with available data were analyzed.

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).

Outcome measures

Measure	Cefiderocol Plus Midazolam n=11 Participants 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.
Area Under the Plasma Concentration-time Curve Over the Dosing Interval τ (8 Hours) (AUC0-τ) of Cefiderocol	355.4 μg*hrs/mL Geometric Coefficient of Variation 20.2

SECONDARY outcome

Timeframe: Day 15

Population: Pharmacokinetics Parameter Population: All participants with at least 1 pharmacokinetics parameter estimated appropriately. Participants with available data were analyzed.

This outcome measure presents the PK of cefiderocol when coadministered with midazolam. CL was calculated as: Dose/AUC0-τ on Day 15.

Outcome measures

Measure	Cefiderocol Plus Midazolam n=11 Participants 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.
CL of Cefiderocol	5.63 liter/hr Geometric Coefficient of Variation 20.2

Adverse Events

Cefiderocol Plus Midazolam

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Cefiderocol Plus Midazolam n=14 participants at risk A total of 2 doses of midazolam and 45 doses of cefiderocol were administered to each participant per specified dosing schedule.
Gastrointestinal disorders Abdominal pain	14.3% 2/14 • Day -1 through Day 23
Gastrointestinal disorders Diarrhoea	14.3% 2/14 • Day -1 through Day 23
Gastrointestinal disorders Nausea	14.3% 2/14 • Day -1 through Day 23
General disorders Infusion site extravasation	50.0% 7/14 • Day -1 through Day 23
General disorders Infusion site pain	28.6% 4/14 • Day -1 through Day 23
General disorders Infusion site phlebitis	28.6% 4/14 • Day -1 through Day 23
General disorders Catheter site pain	14.3% 2/14 • Day -1 through Day 23
General disorders Chills	7.1% 1/14 • Day -1 through Day 23
General disorders Infusion site dermatitis	7.1% 1/14 • Day -1 through Day 23
General disorders Infusion site inflammation	7.1% 1/14 • Day -1 through Day 23
General disorders Non-cardiac chest pain	7.1% 1/14 • Day -1 through Day 23
General disorders Pyrexia	7.1% 1/14 • Day -1 through Day 23
General disorders Vessel puncture site haemorrhage	7.1% 1/14 • Day -1 through Day 23
Immune system disorders Drug hypersensitivity	7.1% 1/14 • Day -1 through Day 23
Infections and infestations Vulvovaginal candidiasis	11.1% 1/9 • Day -1 through Day 23
Investigations Blood lactate dehydrogenase increased	7.1% 1/14 • Day -1 through Day 23
Investigations Transaminases increased	7.1% 1/14 • Day -1 through Day 23
Musculoskeletal and connective tissue disorders Neck pain	7.1% 1/14 • Day -1 through Day 23
Nervous system disorders Headache	14.3% 2/14 • Day -1 through Day 23
Nervous system disorders Somnolence	14.3% 2/14 • Day -1 through Day 23
Nervous system disorders Dizziness	7.1% 1/14 • Day -1 through Day 23
Nervous system disorders Presyncope	7.1% 1/14 • Day -1 through Day 23
Respiratory, thoracic and mediastinal disorders Cough	7.1% 1/14 • Day -1 through Day 23
Respiratory, thoracic and mediastinal disorders Epistaxis	7.1% 1/14 • Day -1 through Day 23
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	7.1% 1/14 • Day -1 through Day 23
Skin and subcutaneous tissue disorders Urticaria	7.1% 1/14 • Day -1 through Day 23

Additional Information

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Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: OTHER