A Phase 1, Open-label, Single-dose Study to Determine the Safety and Pharmacokinetics of Intravenous Cefiderocol/Xeruborbactam (S-649228) in Participants with Renal Impairment

Qpex Biopharma, Inc., a wholly owned subsidiary of Shionogi Inc., is developing a fixed combination antibiotic of cefiderocol, a cephalosporin antibiotic approved in the US for the treatment of complicated urinary tract infections (cUTIs) including pyelonephritis, and hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP), plus an investigational broad-spectrum beta-lactamase inhibitor (BLI), xeruborbactam (QPX7728) to address the need for new antibiotics for the pathogens deemed as urgent or critical threats.

The aim of this study is to compare single-dose intravenous (IV) pharmacokinetics (PK) and safety of the combination of cefiderocol/xeruborbactam (S-649228) in participants with various degrees of stable renal impairment, including those with end-stage renal disease (ESRD), to control participants with normal renal function.

The results from this study will enable the development of appropriate dosing recommendations in patients with impaired renal function.

Objectives:

The objectives of the study are:

1. To assess the impact of mild, moderate, and severe renal impairment, and intermittent hemodialysis (IHD) on the PK of IV cefiderocol and IV xeruborbactam given to participants with stable renal impairment, normal renal function, and ESRD receiving IHD therapy.
2. To evaluate the safety and tolerability of IV cefiderocol and IV xeruborbactam given to participants with stable renal impairment, normal renal function, and ESRD receiving IHD therapy.

Inclusion Criteria:

An individual will be eligible to be included in the study only if all of the following criteria apply:

All participants

• Able to understand the study conduct and tasks required of the participants, sign the informed consent form and willing to cooperate with all tests and examinations required by the protocol.
• Aged 18 to 80 years, inclusive, at the time of consent.
• If male, agrees to be sexually abstinent or agrees to use 2 approved methods of contraception (refer to Inclusion Criterion 4) when engaging in heterosexual activity from Day -1 through 90 days following the last administration of the study intervention, and to not donate sperm during this same period of time. If the sexual partner is surgically sterile, contraception is not necessary.
• If female of childbearing potential, must either be sexually abstinent for 14 days prior to Day -1 and remain so through 30 days following dosing of the study intervention or have been using (or agree to use) 2 acceptable methods of birth control when engaging in heterosexual activity
• If female of childbearing potential, must agree not to donate eggs (ova, oocytes) for the purpose of reproduction from Day -1 through 30 days following the last administration of the study intervention.
• If female of non-childbearing potential, must either be postmenopausal (defined as 12 months spontaneous amenorrhea) with serum follicle stimulating hormone (FSH) level in the laboratory-defined postmenopausal range or have undergone sterilization procedures at least 6 months prior to Day -1; documentation of sterilization procedure must be obtained
• Has a BMI ≥ 18.5 kg/m2 and ≤ 45 kg/m2, inclusive.
• Has negative test results for hepatitis B surface antigen (HBsAg), anti-Hepatitis C virus (HCV) antibody, anti-human immunodeficiency virus (HIV) antibody, and SARS-CoV-2.

Participants with normal renal function:

• Has an eGFR ≥ 90 mL/min calculated using the 2021 CKD-EPI equation adjusted for the participant's BSA at screening
• Meets matching criteria for age, BMI, and gender of pooled renally impaired participants as defined in the protocol.

Participants with renal impairment

• Stable mild to severe renal impairment, as assessed by eGFR calculated using the 2021 CKD-EPI equation adjusted for the participant's BSA at screening
• Is on a stable medication regimen

Participants with ESRD on hemodialysis

• Receiving stable IHD at least 3 times a week for at least 3 months, using an arteriovenous fistula, graft, or catheter
• Is on a stable medication regimen

Exclusion Criteria:

An individual must not meet any of the following exclusion criteria to be eligible to participate in the study:

• Has unstable or new medical condition(s)
• Has had surgery under general anesthesia within the past 3 months prior to Day -1, determined by the investigator to be clinically relevant.
• Documented hypersensitivity reaction or anaphylaxis to any medication.
• History of seizures, convulsions
• Current evidence or history of malignancy
• If female, is pregnant, lactating, or has a positive pregnancy test at screening or Day -1.
• Received any investigational drug within 30 days or 5 half-lives, whichever is longer, of Day -1 for the current clinical study.
• Blood donation or significant blood loss (ie, > 500 mL) within 56 days prior to Day -1.
• Plasma or platelet donation within 14 days prior to Day -1.
• Any acute illness requiring antibiotic drug therapy within 30 days prior to Day -1 or a febrile illness within 7 days prior to Day -1.
• Vigorous exercise from 72 hours prior to Day -1 through the final FU/EOS Visit.
• Positive drug test at the Screening Visit or Day -1
• Positive alcohol test at screening or Day -1 and/or recent history (ie, within 6 months prior to Day -1) of excessive alcohol intake.
• Concurrent use of medications known to affect the elimination of serum creatinine and competitors of renal tubular secretion
• Employees of the investigative site involved in this study.
• Unable or unwilling to adhere to the study-specified procedures and restrictions.
• QTcF interval > 500 msec, previous history or family history of prolonged QT syndrome at screening or Day -1.
• Use of products containing alcohol, caffeine, xanthine, or ephedrine within 24 hours prior to Day -1; use of alcohol 48 hours prior to Day -1; use of proton pump inhibitors (eg, omeprazole and pantoprazole) 7 days prior to Day -1, including both over-the-counter (OTC) and prescription drugs in these categories; or consumption of grapefruit/grapefruit juice, Seville oranges, pomelo, exotic citrus fruits or grapefruit hybrids or juices containing such products within 7 days prior to Day -1.
• Has any clinically significant abnormalities in laboratory values at screening or Day -1, defined in the study protocol.

Participants with normal renal function:

• Abnormal and clinically significant findings on physical examination, medical history, serum chemistry, hematology, or urinalysis per Investigator discretion.

Participants with renal impairment, including those on IHD:

• Abnormal and clinically significant findings on physical examination, medical history, serum chemistry, hematology, or urinalysis per Investigator discretion. Participants in the renal impairment group will have consideration for the degree of renal impairment and presence of comorbidities.
• Has renal disease secondary to hepatic disease (hepatorenal syndrome)