Safety and tolerability.

Cefiderocol was generally well tolerated in the single-dose and multiple-dose studies (Tables 2 and ​and33).

TABLE 2

Incidence of adverse events in the single-dose study^a

AE by system organ class, preferred term	Cefiderocol						Placebo (n = 10)
	100 mg (n = 6)	250 mg (n = 6)	500 mg (n = 6)	1,000 mg (n = 6)	2,000 mg (n = 6)	Total (n = 30)
Any adverse event	1 (1), 16.7	0	1 (2), 16.7	2 (4), 33.3	2 (3), 33.3	6 (10), 20.0	4 (5), 40.0
Gastrointestinal disorders	0	0	1 (2), 16.7	0	1 (1), 16.7	2 (3), 6.7	2 (2), 20.0
Diarrhea	0	0	1 (1), 16.7	0	1 (1), 16.7	2 (2), 6.7	1 (1), 10.0
Abdominal pain	0	0	1 (1), 16.7	0	0	1 (1), 3.3	0
Nausea	0	0	0	0	0	0	1 (1), 10.0
Investigations	1 (1), 16.7	0	0	1 (3), 16.7	1 (1), 16.7	3 (5), 10.0	2 (2), 20.0
Urine positive for white blood cells	0	0	0	1 (1), 16.7	0	1 (1), 3.3	1 (1), 10.0
Blood creatine phosphokinase level increased	0	0	0	1 (1), 16.7	0	1 (1), 3.3	0
Blood present in urine	0	0	0	1 (1), 16.7	0	1 (1), 3.3	0
Urine positive for red blood cells	1 (1), 16.7	0	0	0	0	1 (1), 3.3	0
White blood cell count increased	0	0	0	0	1 (1), 16.7	1 (1), 3.3	0
Blood glucose level increased	0	0	0	0	0	0	1 (1), 10.0
Nervous system disorders	0	0	0	0	0	0	1 (1), 10.0
Dizziness	0	0	0	0	0	0	1 (1), 10.0
Skin and subcutaneous tissue disorders	0	0	0	1 (1), 16.7	1 (1), 16.7	2 (2), 6.7	0
Rash	0	0	0	1 (1), 16.7	1 (1), 16.7	2 (2), 6.7	0

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^aThe data are shown as the number of subjects (number of events), percentage of subjects with adverse events. Denominators for the percentages are the numbers of subjects in the safety population in each treatment group.

TABLE 3

Incidence of adverse events in the multiple-dose study^c

AE by system organ class, preferred term	Cefiderocol				Placebo (n = 10)
	1,000 mg 1st (n = 8)a	1,000 mg 2nd (n = 8)b	2,000 mg (n = 8)b	Total (n = 16)b
Any adverse event	7 (17), 87.5	6 (15), 75.0	6 (13), 75.0	12 (28), 75.0	4 (6), 66.7
Gastrointestinal disorders	0	2 (3), 25.0	1 (1), 12.5	3 (4), 18.8	0
Diarrhea	0	2 (3), 25.0	0	2 (3), 12.5	0
Abdominal pain	0	0	1 (1), 12.5	1 (1), 6.3	0
General disorders and administration site conditions	2 (2), 25.0	1 (1), 12.5	1 (1), 12.5	2 (2), 12.5	0
Pyrexia	2 (2), 25.0	1 (1), 12.5	1 (1), 12.5	2 (2), 12.5	0
Infections and infestations	0	1 (1), 12.5	0	1 (1), 6.3	0
Upper respiratory tract infection	0	1 (1), 12.5	0	1 (1), 6.3	0
Investigations	5 (9), 62.5	4 (9), 50.0	4 (7), 50.0	8 (16), 50.0	4 (6), 66.7
Alanine aminotransferase level increased	1 (1), 12.5	3 (3), 37.5	1 (1), 12.5	4 (4), 25.0	3 (3), 50.0
Aspartate aminotransferase level increased	1 (1), 12.5	3 (3), 37.5	1 (1), 12.5	4 (4), 25.0	1 (1), 16.7
Blood creatine phosphokinase level increased	0	1 (2), 12.5	2 (2), 25.0	3 (4), 18.8	1 (1), 16.7
White blood cell count increased	0	0	2 (2), 25.0	2 (2), 12.5	0
Blood TSH level increased	3 (3), 37.5	0	0	0	0
Blood lactate dehydrogenase level increased	0	1 (1), 12.5	0	1 (1), 6.3	0
Blood urea level increased	1 (1), 12.5	0	0	0	1 (1), 16.7
Urine positive for white blood cells	0	0	1 (1), 12.5	1 (1), 6.3	0
Blood TSH level decreased	1 (2), 12.5	0	0	0	0
Blood present in urine	1 (1), 12.5	0	0	0	0
Nervous system disorders	1 (1), 12.5	0	1 (1), 12.5	1 (1), 6.3	0
Headache	1 (1), 12.5	0	1 (1), 12.5	1 (1), 6.3	0
Respiratory, thoracic, and mediastinal disorders	0	1 (1), 12.5	0	1 (1), 6.3	0
Oropharyngeal pain	0	1 (1), 12.5	0	1 (1), 6.3	0
Skin and subcutaneous tissue disorders	5 (5), 62.5	0	2 (3), 25.0	2 (3), 12.5	0
Rash	5 (5), 62.5	0	2 (3), 25.0	2 (3), 12.5	0

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^aThe study drug (cefiderocol) was contaminated with iodide.

^bThe study drug (cefiderocol) was not contaminated with iodide.

^cThe data are shown as the number of subjects (number of events), percentage of subjects with adverse events. Denominators for the percentages are the numbers of subjects in the safety population in each treatment group.

In the single-dose study, nine adverse events (AEs) reported by six subjects in the cefiderocol groups were considered possibly or probably related to study treatment: diarrhea (two events in two subjects), rash (two events in two subjects), and one event each of abdominal pain, blood present in urine, urine positive for red blood cells, white blood cell count increased, and urine positive for white blood cells. In the placebo group, four AEs reported by three subjects were considered possibly related to study treatment (one event each of diarrhea, dizziness, nausea, and urine positive for white blood cells).

In the multiple-dose study, 16 AEs reported by seven subjects in the cefiderocol 1,000-mg 1st group were considered possibly or probably related to the study treatment: rash (5 events in five subjects), a blood thyroid-stimulating hormone (TSH) level increase (3 events in three subjects), pyrexia (2 events in two subjects), and 1 event each of an alanine aminotransferase level increase, an aspartate aminotransferase level increase, a blood TSH level decrease, a blood urea level increase, urine present in blood, and headache. In the cefiderocol 1,000-mg 2nd and 2,000-mg groups, 22 AEs reported by 12 subjects were considered possibly or probably related to the study treatment: an alanine aminotransferase level increase (4 events in four subjects), an aspartate aminotransferase level increase (3 events in three subjects), diarrhea (3 events in two subjects), rash (3 events in two subjects), pyrexia (2 events in two subjects), a white blood cell count increase (2 events in two subjects), and 1 event each of abdominal pain, a blood creatine phosphokinase level increase, headache, oropharyngeal pain, and urine positive for white blood cells. TSH abnormalities were reported only in the 1,000-mg 1st group.

In the multiple-dose study, there was a higher frequency of rash (five events in five of eight subjects [62.5%]) in the 1,000-mg 1st group than in the 1,000-mg 2nd (no events) and 2,000-mg groups (three events in two of eight subjects [25%]). Allergy tests conducted for the two subjects with rash in the 2,000-mg group showed levels almost within normal ranges, and measurement of cefiderocol-specific immunoglobulin G (IgG) and immunoglobulin E (IgE) yielded nondetectable levels.

All of the AEs were mild in intensity, except for one AE that was moderate (pyrexia in the 1,000-mg 1st group). There were no deaths, serious AEs, abnormal 12-lead or continuous electrocardiogram (ECG) findings, or abnormal changes in vital signs, except in the subjects in the multiple-dose study with pyrexia. One subject in the cefiderocol 1,000-mg 2nd group withdrew due to pyrexia on the last day of study drug administration. There was no dose-response trend in the incidence of AEs, which were relatively evenly spread among the dose groups, including the placebo groups.

Blood iron and total iron-binding capacity levels.

In the single-dose study, the mean value of blood iron was slightly below the lower limit of normal (LLN) (reference range, 80 to 199 μg/dl for males, 70 to 179 μg/dl for females) in the 500-mg group on day 5 (71.2 μg/dl) and day 8 (68.3 μg/dl) and in the 1,000-mg group on day 8 (76.8 μg/dl); no mean value below the LLN was observed in the 2,000-mg group or the placebo group. In the multiple-dose study, the mean value of blood iron was slightly below the LLN in the 1,000-mg 1st group on days 5, 11, and 17 and in the 1,000-mg 2nd group on days 5, 11, 13, 14, and 17; no mean value below the LLN was observed in the 2,000-mg group or the placebo group (Table 4).

Pharmacokinetics in plasma.

The mean plasma concentration profiles of unchanged cefiderocol after the infusion of single doses ranging from 100 to 2,000 mg are shown in Fig. 1. A summary of the values of the PK parameters following the single-dose administration of cefiderocol is shown in Table 5. Geometric mean values ranged from 7.76 to 156 μg/ml (coefficient of variation for geometric mean [CV], 4.6% to 10.7%) for the maximum plasma concentration (C_max), 17.03 to 388.9 μg · h/ml (CV, 6.3% to 22.5%) for the area under the concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration after dosing (AUC_0–last), and 17.49 to 389.7 μg · h/ml (CV, 6.3% to 22.7%) for the area under the concentration-time curve extrapolated from time zero to infinity (AUC_0–inf), suggesting low to moderate interindividual variability for plasma exposure in all dose groups. The geometric mean plasma terminal elimination half-life (t_1/2,z) of cefiderocol was 1.98 to 2.74 h. Estimates of the slopes for the C_max, AUC_0–last, and AUC_0–inf of cefiderocol were 1.00 (95% confidence interval [CI], 0.965 to 1.04), 1.04 (95% CI, 0.983 to 1.09), and 1.03 (95% CI, 0.975 to 1.08), respectively, indicating dose-proportional increases in these parameters across the dose range of 100 to 2,000 mg. Statistical analyses showed no dose dependency for t_1/2,z, total clearance (CL), the mean residence time (MRT), the urinary excretion ratio relative to the dose over 48 h (Feu_0–48), or renal clearance (CL_R).

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FIG 1

Mean (SD) plasma concentrations of cefiderocol following single-dose administration.

Figure 2 shows the mean plasma concentration profiles of cefiderocol following multiple infusions in the 1,000-mg 1st, 1,000-mg 2nd, and 2,000-mg groups. The mean trough concentrations from 48 to 192 h after the start of the initial infusion were 5.18 to 5.60, 5.11 to 5.39, and 9.66 to 13.0 μg/ml for the 1,000-mg 1st, 1,000-mg 2nd, and 2,000-mg groups, respectively. A summary of the values of the PK parameters for cefiderocol after multiple-dose administration is shown in Table 6. Plasma concentration profiles and linear regression for plasma trough concentrations indicated that steady state was achieved within 1 day after the initiation of multiple dosing (day 3). Plasma concentrations were similar in the 1,000-mg 1st and 1,000-mg 2nd groups. The ratios of C_max and the area under the concentration-time curve over dosing interval τ (AUC_0–τ) between dose groups on day 10 were close to the dose ratio (i.e., 2), suggesting dose-proportional increases in C_max and AUC_0–τ following multiple dosing. Accumulation ratios of C_max and AUC with dosing every 8 h (q8h) were 1.069 and 1.053, respectively, at 1,000 mg and 1.084 and 1.164, respectively, at 2,000 mg. The comparisons of AUC (AUC_0–inf on day 1, AUC_0–τ on day 10), CL, and CL_R between days 1 and 10 indicated no change in PK with multiple dosing.

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FIG 2

Mean (SD) plasma concentrations of cefiderocol following multiple-dose administration at 0 to 24 h (top) and 216 to 240 h (bottom) after the start of the initial infusion.

In the single-dose groups, the plasma concentrations of cefiderocol were below the lower limit of quantitation (BLQ) in most samples after 12 h at 100 mg, 16 h at 250 mg, 24 h at 500 and 1,000 mg, and 36 h at 2,000 mg. In the multiple-dose groups, the plasma cefiderocol concentration was BLQ in most samples after 24 h in both 1,000-mg groups and 36 h in the 2,000-mg group.

Urinary excretion.

The mean urine concentration profiles of unchanged cefiderocol after the infusion of single doses ranging from 100 to 2,000 mg are shown in Fig. 3. Dose-dependent increases in the urine concentrations appeared across the dose range of 100 to 2,000 mg. The geometric mean urinary excretion ratio relative to the dose of cefiderocol ranged from 61.5% to 68.4% unchanged drug product (Fig. 4). The amount of cefiderocol metabolites was estimated to be less than 10%, as described below. The urine concentration of cefiderocol was BLQ in most urine samples collected from 24 to 48 h in all of the single-dose groups. In the multiple-dose groups, all urine samples had detectable levels of cefiderocol above the lower limit of quantitation at the nominal sampling time.

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FIG 3

Mean (SD) urine concentrations of cefiderocol following single-dose administration.

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FIG 4

Mean (SD) fraction of cefiderocol dose excreted in urine following single-dose administration.

Study design.

This was a phase 1, single-center, randomized, double-blind, placebo-controlled study conducted in two parts: a single-ascending-dose study and a multiple-ascending-dose study. The single-dose study was planned to include up to six single doses of cefiderocol in six cohorts (100, 250, 500, 1,000, 2,000, and 4,000 mg), but dose escalation to the highest dose (4,000 mg) was not performed because a lower dose achieved the prespecified stopping criteria exposure >10-fold lower than the no-observed-adverse-event level in rats (plasma concentration at the completion of dosing = 1,660 μg/ml). A total of 40 healthy Japanese males and females (6 individuals receiving the active drug and 2 individuals receiving a placebo per cohort) participated in the single-dose study, with 3, 1, and 1 postmenopausal females being used in the 500-mg, 1,000-mg, and 2,000-mg cohorts, respectively. Eligible subjects were admitted to the study center 1 day prior to administration, were confined to the study center until day 3, and returned to the study center on days 4, 5, and 8 ± 1 for follow-up.

The multiple-dose study was planned to include up to two doses of cefiderocol (1,000 and 2,000 mg) in two groups. It was discovered that the study drug was contaminated with 0.36% iodide (which is a level lower than the detection limit by traditional elemental analysis) before the start of the multiple-dose study. Consequently, a second 1,000-mg group with purified study drug was added to the multiple-dose study after the 1,000-mg 1st group finished the study. The study with the 1,000-mg 2nd group was conducted with study drug that was free of iodide, which was removed by additional purification. The study therefore included five groups that received study drug once at 100, 250, 500, 1,000, or 2,000 mg (which received iodide-contaminated study drug) and three groups that received the study drug every 8 h (q8h) for 10 days: the 1,000-mg 1st group (which received iodide-contaminated study drug), the 1,000-mg 2nd group (which received iodide-free study drug), and the 2,000-mg group (which received iodide-free study drug). A total of 30 healthy males (8 individuals receiving the active drug and 2 individuals receiving a placebo per cohort) participated in the multiple-dose study, with two Caucasians being included in each of the 1,000-mg-dose groups and three Caucasians being included in the 2,000-mg-dose groups. Eligible subjects were admitted to the study center 1 day prior to administration, were confined to the study center until day 12, and returned to the study center on days 13, 14, and 17 ± 1 for follow-up visits.

Safety evaluation.

Safety was assessed through assessment of adverse events (AEs), physical examinations, assessment of vital signs, 12-lead and continuous electrocardiogram (ECG) recordings, and performance of laboratory tests (hematology; blood chemistry, including iron and total iron-binding capacity; and urinalysis). Thyroid function tests (tests for thyroid-stimulating hormone [TSH], free thyroxine, and free triiodothyronine levels) and allergy tests (tests for the blood tryptase level, serum complement activity, and the plasma histamine level) were added for the multiple-dose study in response to the iodide contamination in the initial drug supply, and additional immunological tests (tests for cefiderocol-specific immunoglobulin G [IgG] and immunoglobulin E [IgE]) were conducted for two subjects in the 2,000-mg cohort in the multiple-dose study who experienced a rash during the study. All safety data collected were assessed for severity and relationship to the study treatment. All AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 15.0.

Sample collection and analysis.

For the single-dose study, plasma samples were collected prior to infusion (0 h) and at 0.5 (during infusion), 1.0 (just before completion of infusion), 1.25, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 8.0, 10, 12, 16, 24, 36, and 48 h after the start of infusion. Urine samples were collected at 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 24, and 24 to 48 h from the start of the infusion.

For the multiple-dose study, plasma samples were collected as follows: at 0, 0.5, 1.0, 1.25, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 8.0, 10, 12, and 16 h from the start of the first (morning) infusion on day 1; prior to the morning infusion (0 h) on days 2, 3, 5, 8, 9; and at 0, 0.5, 1.0, 1.25, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 8.0, 10, 12, 16, 24, 36, and 48 h from the start of the final (morning) infusion on day 10. Urine samples were collected at 0 to 8 and 8 to 24 h from the start of the first (morning) infusion on day 1 and at 0 to 8 and 8 to 24 h from the start of the final (morning) infusion on day 10.

The concentrations of cefiderocol in human plasma and urine were determined by a liquid chromatography (LC)-tandem mass spectrometry (MS/MS) method (17). The lower limit of quantification of cefiderocol was 0.1 μg/ml in plasma and 1 μg/ml in urine. Partial validation for changing instrumentation was performed using Qtrap 5500 and Triple Quad 5500 mass spectrometers. The assay was linear from 0.1 to 100 and 1 to 1,000 μg/ml for plasma and urine, respectively. The precision of the assay was 4.3% to 11.2% and 1.0% to 8.8% for plasma and urine, respectively. The accuracy of the assay was −7.0% to 7.0% and −6.4% to 9.0% for plasma and urine, respectively.

Pharmacokinetic and statistical analyses.

The following PK parameters were calculated by noncompartmental methods using WinNonlin software (version 6.2.1; Certara L.P., Princeton, NJ) on the basis of plasma and urine concentration data: the maximum plasma concentration (C_max), the time to the maximum plasma concentration (T_max), the area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing (AUC_0–last), the area under the concentration-time curve extrapolated from time zero to infinity (AUC_0–inf), the area under the concentration-time curve over dosing interval τ (AUC_0–τ), the terminal elimination half-life (t_1/2,z), the mean residence time (MRT), total clearance (CL), the urinary excretion ratio relative to the dose over 48 h (Feu_0–48), and renal clearance (CL_R).

The dose proportionality of the PK parameters was examined by using a power model. Dose proportionality, dose independency, the effect of multiple doses, and the accumulation ratio of PK parameters were examined by analysis of variance. Achievement of steady state was assessed by visual inspection of the plots and by linear regression for plasma trough concentrations. SAS software (version 9.1; SAS Institute Inc., Cary, NC) was used for statistical analyses.

This study was supported by and conducted with funds provided by Shionogi & Co., Ltd. (Osaka, Japan), and GlaxoSmithKline (Brentford, Middlesex, UK). Medical editing was performed by Erik Sakowski of Phase Five Communications, Inc., supported by Shionogi & Co., Ltd.

We express our sincere gratitude to the subjects for their participation in this study and to the physicians who conducted the study at the CPC Clinical Trial Hospital (Kagoshima, Japan) in accordance with the protocol. We also thank all those who acted as coworkers and monitors for their dedicated work.

We declare no conflicts of interest.