Pharmacokinetics of Fluconazole in Pediatric and Adolescent Patients with Invasive Fungal Infections: Oral and Intravenous Administration

The primary objective of this study is to establish an improved **fluconazole** dosing regimen for pediatric and adolescent patients aged 2-18 years with invasive fungal infections. This is clinically relevant as it aims to optimize therapeutic outcomes and minimize potential adverse effects in this vulnerable population, ensuring effective prophylaxis or therapy against fungal infections.

Secondary objectives include:

• Exploring the role of renal function on the clearance of fluconazole, which is crucial for understanding how kidney function affects drug elimination and dosing adjustments.
• Investigating the bioavailability of oral fluconazole versus intravenous fluconazole in pediatric patients, which is important for determining the most effective and convenient route of administration.

The clinical trial focuses on establishing an improved **fluconazole** dosing regimen for pediatric and adolescent patients aged 2-18 years. The study population includes both male and female subjects who are being treated with fluconazole for prophylaxis or treatment of an invasive **fungal infection**. Participants are required to have a central venous catheter or arterial line for blood sampling. The trial involves a vulnerable population, as it includes children and adolescents. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants are within the specified age range and are receiving the necessary medical management for their condition.

The clinical trial is designed to evaluate the pharmacokinetics of **fluconazole** administered either orally or intravenously to children and adolescents aged 2-18 years with invasive fungal infections. The study aims to establish an improved dosing regimen for this population through population pharmacokinetic (pop-PK) modeling. The trial is structured as a Phase IV, observational study, with a randomized, double-blind, controlled design. The estimated duration of the trial is from March 1, 2022, to September 30, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, treatment with **fluconazole** for prophylaxis or therapy, and management with a central venous catheter or arterial line. Follow-up visits will be scheduled to monitor pharmacokinetic parameters, including clearance, volume of distribution, and exposure described by the area under the concentration-time curve (AUC). The end-of-study visit will conclude the participant's involvement, which is expected to last up to 12 months, depending on the treatment period.

Participants may be withdrawn from the study if they do not adhere to the protocol, experience adverse effects, or if the investigator deems it necessary for their safety. The study will explore covariates such as renal clearance and body weight, as well as the oral bioavailability of **fluconazole**. The trial will utilize various formulations of **fluconazole**, including capsules, oral suspension, and solution for infusion, with a maximum daily dose of 800 mg and a total dose not exceeding 365 mg over the treatment period.

The clinical trial involves the administration of several formulations of **fluconazole**, a chemical compound used as an antifungal agent. The first experimental medication is Fluconazol Accord 50 mg capsules, hard. This pharmaceutical form is a hard capsule, administered orally. The dosage is 50 mg per capsule, with a maximum daily dose of 800 mg. The treatment period can extend up to 12 weeks, depending on the patient's response and clinical condition. Participant compliance is monitored through regular assessments and dosage adjustments as necessary.

Another formulation used in the trial is Diflucan I.V. 2 mg/ml, a solution for infusion. This preparation is administered via intravenous infusion, allowing for direct entry into the bloodstream. The concentration is 2 mg/ml, with a maximum daily dose of 800 mg. The treatment duration is also up to 12 weeks. This route of administration is particularly beneficial for patients who may have difficulty with oral intake or require rapid therapeutic levels of the medication.

Additionally, Diflucan 100 mg, capsule, hard, is included in the study. This formulation is similar to the Fluconazol Accord capsules but contains a higher dosage of 100 mg per capsule. It is also administered orally, with the same maximum daily dose of 800 mg and a treatment period of up to 12 weeks. Regular monitoring ensures adherence to the dosing schedule and allows for any necessary adjustments.

The trial also incorporates Diflucan 10 mg/ml, poeder voor orale suspensie, an oral suspension form of fluconazole. This formulation is designed for oral administration, providing an alternative for patients who may have difficulty swallowing capsules. The suspension allows for flexible dosing, with a maximum daily dose of 800 mg and a treatment period of up to 12 weeks. Compliance is tracked through patient diaries and periodic evaluations.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this trial. The focus is on optimizing the dosing regimen of fluconazole for pediatric and adolescent patients with invasive fungal infections. The study aims to establish an improved dosing protocol, ensuring effective prophylaxis or therapy while minimizing potential side effects.

Efficacy in this clinical trial will be assessed through the evaluation of **fluconazole** pharmacokinetics in pediatric and adolescent patients aged 2-18 years. The primary endpoints include the development of a population pharmacokinetic (pop-PK) model to describe pharmacokinetic parameters such as clearance (CL), volume of distribution (Vd), and exposure, which is quantified by the area under the concentration-time curve (AUC). These parameters will be measured and analyzed to establish an improved dosing regimen for the target population.

Secondary endpoints involve the exploration of covariates that may influence the primary study parameters. These covariates include renal clearance and body weight. Additionally, the study will investigate the oral bioavailability (F) of **fluconazole**, which refers to the percentage of the drug that is systemically available after oral administration compared to intravenous administration. The study is observational, and potential covariates will be explored to understand their impact on the pharmacokinetic parameters.