Pharmacokinetics and Safety Evaluation of Cefiderocol in Hospitalized Neonates with Suspected or Confirmed Aerobic Gram-negative Bacterial Infections

The primary objective of this study is to assess the **pharmacokinetics** of cefiderocol following both single-dose and multiple-dose administration in hospitalized pediatric patients from birth to less than 3 months of age with suspected or confirmed aerobic Gram-negative bacterial infections. This includes conditions such as complicated urinary tract infections (cUTI), complicated intra-abdominal infections (cIAI), hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP), and bloodstream infections/sepsis. Understanding the pharmacokinetics is crucial for optimizing dosing regimens and ensuring effective and safe treatment in this vulnerable population.

Secondary objectives include:

• Assessing the safety and tolerability of cefiderocol after single-dose administration in the same patient population.
• Evaluating the safety and tolerability of cefiderocol after multiple-dose administration.
• Evaluating all-cause mortality at Day 28.

The clinical trial involves a total of **20 participants** who are hospitalized pediatric patients from birth to less than 3 months of age, with suspected or confirmed **aerobic Gram-negative bacterial infections**. The study population includes both male and female infants, and enrollment is not restricted to premature infants, provided they have a gestational age of at least 26 weeks, a postnatal age of 0 to 3 months, and a minimum weight of 1 kg. Participants require systemic intravenous antibiotic treatment for infections such as complicated urinary tract infections (cUTI), complicated intra-abdominal infections (cIAI), hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), bloodstream infections (BSI), or sepsis. The trial population was selected based on the need for systemic IV antibiotic treatment and the ability to provide written informed consent by the parent(s) or legally authorized representative(s). The study does not impose specific lifestyle considerations such as diet or physical activity, given the age and health status of the participants.

The clinical trial is designed as a **single-arm, open-label** study to evaluate the pharmacokinetics, safety, and tolerability of **cefiderocol** in hospitalized pediatric patients from birth to less than 3 months of age with suspected or confirmed aerobic Gram-negative bacterial infections. The trial is categorized as a Phase 4 study, focusing primarily on pharmacokinetics and safety. The study will involve the administration of cefiderocol as a **solution for infusion**. The trial is expected to commence on November 1, 2023, and conclude by August 30, 2024.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, weight, and the requirement for systemic intravenous antibiotic treatment. The trial will include both single-dose and multiple-dose phases. The primary endpoints will assess the maximum concentration (Cmax), area under the curve (AUC), and half-life (t1/2) of cefiderocol after administration. Secondary endpoints will monitor adverse events, vital signs, physical examinations, clinical laboratory assessments, and mortality.

The expected duration of participant involvement is up to 14 days, corresponding to the maximum treatment period with cefiderocol. Conditions that may lead to early termination from the study include the occurrence of significant adverse events or withdrawal of consent by the parent(s) or legally authorized representative(s). The study aims to provide critical data on the pharmacokinetics and safety profile of cefiderocol in this vulnerable pediatric population, contributing to informed clinical decision-making for treating aerobic Gram-negative bacterial infections in infants.

The clinical trial involves the administration of **Fetcroja**, a pharmaceutical product containing the active substance **cefiderocol**. This medication is provided in the form of a **powder for concentrate for solution for infusion**. The product is intended for intravenous infusion and is specifically designed for use in pediatric patients from birth to less than 3 months of age. The maximum daily dose is 180 mg/kg, with a total maximum dose of 2520 mg/kg over a treatment period not exceeding 14 days. The product is manufactured by SHIONOGI B.V. and is authorized for use in the European Union under the marketing authorization number EU/1/20/1434/001. The formulation remains unchanged except for secondary packaging and labeling adjustments to reflect its use in the clinical study. Additionally, alternative reconstitution and dilution methods are employed to prepare suitable doses for pediatric administration.

In this study, **cefiderocol** is administered via infusion, and the dosing schedule is determined based on the pharmacokinetic assessment of the drug in the target population. The trial aims to evaluate the pharmacokinetics, safety, and tolerability of cefiderocol in hospitalized pediatric patients with suspected or confirmed aerobic Gram-negative bacterial infections. The study does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance with the dosing regimen is monitored throughout the study to ensure accurate assessment of the drug's pharmacokinetic profile.

The efficacy of the clinical trial will be assessed through primary and secondary endpoints. The primary endpoints include the measurement of **Cmax** (maximum concentration), **AUC0-inf** (area under the curve from time zero to infinity), and **t1/2** (half-life) after a single dose of cefiderocol. Additionally, these parameters will be evaluated after a minimum of four doses of cefiderocol, specifically **Cmax**, **AUC0-τ** (area under the curve over the dosing interval), and **t1/2**. These pharmacokinetic parameters will provide insights into the drug's absorption, distribution, metabolism, and excretion in the pediatric population.

Secondary endpoints will focus on safety and tolerability, including the monitoring of adverse events, vital signs, physical examinations, clinical laboratory assessments, and mortality. These assessments will be conducted throughout the trial to ensure comprehensive safety monitoring. The trial is designed to evaluate the pharmacokinetics of cefiderocol in hospitalized pediatric patients from birth to less than 3 months of age with suspected or confirmed aerobic Gram-negative bacterial infections. The study will provide critical data on the drug's behavior in this specific patient population, contributing to the understanding of its efficacy and safety profile.