Evaluation of Pharmacokinetics, Safety, and Tolerability of Intravenous and Oral Posaconazole in Pediatric Patients with Invasive Fungal Infections

The primary objective of this study is to estimate the **pharmacokinetics** (PK) of **posaconazole** (POS) in intravenous (IV) and powder for oral suspension (PFS) formulations in pediatric participants under 2 years of age. Understanding the PK profile in this age group is clinically relevant as it informs dosing strategies and ensures therapeutic efficacy while minimizing potential toxicity in treating invasive fungal infections.

Secondary objectives include: - Comparing the exposures to POS in neonates and infants under 2 years of age to those from adult and older pediatric populations (Panel B only). - Evaluating the safety and tolerability of POS in participants under 2 years of age (Panels A and B separately). - Assessing all-cause mortality at Day 28 in participants treated with POS (Panel B only). - Evaluating the need for additional antifungal therapy (Panel B only).

The clinical trial involves a total of **19 participants** who are less than 2 years of age, encompassing both male and female subjects. The study population is specifically selected to include individuals undergoing treatment for possible, probable, or proven invasive **fungal infection**. Participants are required to have a central line in place or planned before the initiation of the intravenous study intervention and must have a body weight of at least 500 grams. The trial population is considered vulnerable due to the young age of the participants. The selection process ensures that participants have provided documented informed consent through a legally acceptable representative. The study does not specify any particular lifestyle considerations such as diet or physical activity for the participants.

The clinical trial is designed to evaluate the **pharmacokinetics**, safety, and tolerability of **posaconazole** in pediatric participants from birth to less than 2 years of age with possible, probable, or proven invasive **fungal infection**. This is a Phase 2, open-label, single-arm, sequential-panel study. The trial involves two formulations of posaconazole: intravenous (IV) and powder for oral suspension (PFS). The study is structured into two panels, A and B, with specific objectives and endpoints for each. The trial is expected to run from April 17, 2020, to September 22, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as body weight and the presence of a central line. The study will include follow-up visits to monitor the pharmacokinetic parameters and safety outcomes. The primary endpoints include the average concentration (Cavg), maximum concentration (Cmax), and time to maximum concentration (Tmax) of single-dose IV posaconazole in Panel A, and similar parameters for multiple-dose IV and PFS posaconazole in Panel B. Secondary endpoints focus on comparing pharmacokinetic data with other populations and assessing adverse events.

The expected length of participant involvement varies, with a maximum treatment period of 84 days for the IV formulation and 77 days for the oral suspension. Conditions that may lead to early termination from the study include the occurrence of adverse events or the need for systemic antifungal therapy other than posaconazole. The study aims to provide comprehensive data on the pharmacokinetics and safety of posaconazole in this young population, contributing to the understanding of its use in treating invasive fungal infections in pediatric patients.

The clinical trial involves the administration of **Noxafil 300 mg concentrate for solution for infusion**, which contains the active substance **posaconazole**. This experimental medication is provided in the form of a concentrate for solution for infusion and is administered via **intravenous injection**. The maximum daily dose is 600 mg, with a total maximum dose of 25,500 mg over a treatment period of up to 84 days. The pharmaceutical product is manufactured by Merck Sharp & Dohme BV and is classified under the ATC code J02AC04. The administration of this medication is monitored to ensure participant compliance with the dosing schedule.

Additionally, the study includes the use of **Posaconazole** in the form of an **oral suspension**. This formulation is also based on the active substance posaconazole and is administered orally. The maximum daily dose for the oral suspension is 240 mg, with a total maximum dose of 18,480 mg over a treatment period of up to 77 days. This product is manufactured by Merck & Co. Inc. and is identified by the sponsor product code MK-5592. The oral suspension is used to evaluate the pharmacokinetics, safety, and tolerability in pediatric participants. Compliance with the oral dosing schedule is similarly monitored throughout the trial.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial documentation. The focus of the study is to assess the pharmacokinetics of the intravenous and oral formulations of posaconazole in pediatric participants with possible, probable, or proven invasive fungal infection. The trial is designed to ensure rigorous monitoring of drug administration and participant adherence to the prescribed dosing regimens.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints focused on the pharmacokinetics of **posaconazole** in pediatric participants under 2 years of age with invasive fungal infections. The primary endpoints include the average concentration (Cavg), maximum concentration (Cmax), time to maximum concentration (Tmax), area under the plasma concentration-time curve from dosing to 24 hours postdose (AUC0-24), clearance (CL), and area under the plasma concentration-time curve from dosing to infinity (AUC0-∞) for both single-dose and multiple-dose intravenous (IV) and powder for oral suspension (PFS) formulations of **posaconazole**. These parameters will be measured in two panels: Panel A for single-dose IV and Panel B for multiple-dose IV and PFS.

Secondary endpoints will evaluate the Cavg of IV **posaconazole** in neonates and infants compared to adults and older pediatric populations, as well as safety-related outcomes such as the percentage of participants experiencing one or more adverse events (AEs), drug-related AEs, discontinuation due to AEs, all-cause mortality through 28 days, and the need for systemic antifungal therapy other than **posaconazole** during the study period. These assessments will be conducted using validated pharmacokinetic methods and safety monitoring protocols, ensuring comprehensive evaluation of the drug's efficacy and safety profile in the target population.