A Physiologically-Based Pharmacokinetic Model to Predict Posaconazole Suspension Exposure and Optimize Dosing Strategy in Pediatric Hematology Patients: Incorporating the Impact of Food Intake.

OBJECTIVE

This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model for posaconazole oral suspension in pediatric hematology patients to predict systemic exposure and optimize dose regimens that incorporate food intake.

METHODS

A PBPK model was established and validated in adults. The model was then extrapolated to pediatric patients by integrating age-specific physiological parameters. The pediatric model was validated using published data and local therapeutic drug monitoring results. The validated model was employed to simulate posaconazole exposure across different age groups, dosing regimens, and meal conditions.

RESULTS

The adult PBPK model showed good predictability, with fold errors within 0.5-2.0 and a geometric mean fold error < 2.0. Sensitivity analysis identified the bile salt solubilization ratio, gastric pH, and hepatic UGT1A4 as critical determinants. The pediatric model accurately predicted plasma concentrations, with a mean absolute prediction error of 12.3%. Simulations revealed that achieving prophylactic trough concentration (Cmin) is challenging under fasted conditions, while fed administration significantly increases Cmins. Cmins increased with age and meal fat/calorie content, but no significant further increase was observed across all age groups beyond 6 mg/kg dose levels under fed conditions, with this plateau pattern consistent for both three- and four-times daily regimens. The oral suspension was unreliable in children aged < 2 years. In contrast, a high-fat, high-calorie meal was necessary for children aged 2-6 years, and a moderate-fat, moderate-calorie meal for those aged 7-12 years, whereas a low-fat, low-calorie meal was sufficient for those aged ≥ 13 years.

CONCLUSION

This study successfully developed and validated a PBPK model for posaconazole suspension in pediatric hematology patients, which could serve as a supportive in silico tool for model-informed dose optimization in this population. Further prospective clinical validation is still required to support its real-world dosing decision application.