Age-Driven Physiologically Based Pharmacokinetic Modeling of Empagliflozin: Toward Precision Dosing in Youth

Type 2 diabetes mellitus (T2DM) is a multifactorial disease that affects both adults and children. Treating T2DM in children poses a challenge because of the difficulties in conducting clinical trials in this special population. Empagliflozin (EMPA) is an antidiabetic drug belonging to the class of sodium-glucose cotransporter 2 (SGLT2) inhibitors and reversibly inhibits glucose reabsorption in the proximal tubules of the kidneys. This drug is a great candidate for treating T2DM in children due to its action on diabetes and other effects such as cardio- and nephroprotection. Despite its therapeutic advantages, the most appropriate dose for the treatment of T2DM in children is still unknown. In this context, new methodological approaches (NAMs) are necessary to overcome these obstacles. Physiologically based pharmacokinetic modeling (PBPK) emerges as a promising and regulatory-accepted approach that can be used to predict the most suitable dose for children. Therefore, the aim of this study was to construct the PBPK model for the oral administration of EMPA in children with healthy and obese weights. Following a literature search, pharmacokinetic and physicochemical parameters of the drug, along with physiological characteristics from selected studies for validation, were obtained for the model development. A PBPK model of EMPA was developed and verified in the adult population by comparing the simulated plasma exposure to the observed data. After validation for healthy adults, the model was scaled for children with healthy and obese weights according to the WHO metrics. The parameters that showed the most significant changes were the C _max and AUC values. In children with healthy weights, C _max was 1.93 and 1.39 times higher in the 10-12 year-old and 13-14 year-old groups, respectively, compared to adults receiving a 10 mg dose. Similarly, AUC increased by 1.81 and 1.48 times in the 10-12 year-old and 13-14 year-old groups, respectively, among healthy children. In obese children aged 10-12, C _max and AUC were altered, showing increases of 1.77 and 1.81 times, respectively. The developed and validated empagliflozin PBPK model in adults provided a robust basis for extending research to pediatric populations. Simulations indicated the need for dose adjustments in pediatric patients, particularly for healthy children aged 10-14 and obese children aged 10-12. These adjustments are essential to minimizing adverse effects, ensuring the safe and effective use of empagliflozin in these age groups.