Assessment of Inter-Individual Pharmacokinetic Variability of Voriconazole Based on Bile Salt Disparities using POP-PK Modeling

Background and Objectives: Voriconazole is a powerful biopharmaceutics classification system (BCS) class II antifungal agent with vast inter-individual pharmacokinetic variability. Bile salts have recently emerged as potential contributors to such variations. Based on population PK modeling and in-vitro biorelevant dissolution investigations, the current study intends to evaluate the inter-individual variability of voriconazole in pediatrics. Methods: All models were developed using PK-Sim software. A simulated population consisting of 100 pediatric individuals was established following the baseline model development. Further, experimentally obtained in-vitro dissolution data of voriconazole based on the bile salt differences representing different pediatric age groups were incorporated into a qualified pediatric model. Simulated plasma concentration-time profiles were then evaluated by comparing model-predicted parameters with that of the baseline model to draw inferences. Result: Each model was created and validated successfully. The pediatric subjects were shown to have larger inter-individual variability than adult subjects. Additionally, simulations based on individual parameter estimations from the final model showed that after administering a 4 mg/kg peroral dose of voriconazole, the anticipated Cmax values of the adult model were within a two-fold range compared to that of the pediatric model. However, upon comparison, the model-predicted population pk profiles of children, infants, and neonates showed minimal variations in the Cmax values. Conclusion: In pediatrics, voriconazole inter-individual variability was significantly influenced by the concentration of gut bile salts. Furthermore, the present research can be carried forward along with population PK modeling and sufficient clinical data for dose recommendations in special populations as well as in diseased conditions.