Physiologically Based Pharmacokinetic Modeling to Refine Dosing of Posaconazole in Young Children.

Abstract

Purpose: Posaconazole is a broad-spectrum antifungal for treating and preventing invasive fungal infections (IFIs) in immunocompromised individuals, including children as young as 2 years. Available in delayed-release (DR) oral suspension, intravenous formulation, and older immediate-release (IR) formulation (off-label in younger children), dosing harmonization across age groups and formulations remains inconsistent. This inconsistency arises from the unique physiology of young children and posaconazole's pH-dependent absorption. Limited pharmacokinetic (PK) data for children under 2 years complicates dosing, as absorption, distribution, metabolism, and excretion processes are underdeveloped and age-dependent. This work aims to harmonize pediatric dosing for children aged 2 to 7 years and extend dosing guidance for those aged 6 months to 2 years using physiologically-based PK (PBPK) modeling.

Methods: An adult PBPK model was created using posaconazole's physicochemical properties and ADME characteristics with virtual populations from PK-Sim. Calibrated with single-dose data from healthy subjects, the model was verified by predicting PK following multiple doses in adults at risk for IFIs. The model was then scaled to children, accounting for developmental anatomy and physiology, including UGT1A4 ontogeny. The pediatric model was evaluated against observed data from children aged 2 to 7 years. Simulations were conducted to harmonize dosing across formulations and extend dosing to children as young as 6 months, acknowledging standard plasma concentration targets for treatment of IFIs (1000 ng/mL) as well as prophylaxis (700 ng/mL).

Findings: The pediatric model adequately captured observed PK data from literature following all three formulations. The IR oral suspension is impractical and likely subtherapeutic for most children under 7 years due to solubility limits. Intravenous doses of 11-13 mg/kg once daily (QD) may be optimal for treatment, and 8 to 9 mg/kg QD for prophylaxis, varying by age. Oral DR suspension doses of 12 to 14 mg/kg QD for treatment and 8.5 to 10 mg/kg QD for prophylaxis may be optimal, also age-dependent. Dividing the total daily dose by a factor of 0.7 and administering twice daily can achieve similar trough levels.

Implications: PBPK modeling for posaconazole bridges the gap between PK principles and clinical practice, potentially improving therapeutic outcomes and minimizing risks associated with inadequate dosing in pediatric patients.