Application of population pharmacokinetic modeling of SVG-101 to evaluate proper dose selection

Everolimus, an inhibitor of the mammalian target of the rapamycin signaling pathway, is used to treat tuberous sclerosis complex (TSC), certain cancers, and organ transplantation. Although a dispersible formulation has been approved for pediatric patients with TSC-associated seizures, no dispersible everolimus formulation has been approved for adults with swallowing difficulties. This study aimed to evaluate the pharmacokinetics (PK) of a newly developed dispersible everolimus tablet (SVG101) in healthy adult males and determine an optimal dosing regimen to achieve therapeutic trough concentrations. This randomized, open-label, single-dose, 2 × 2 crossover study included 26 healthy Korean males. The participants received either the reference tablet or SVG101, with a minimum 10-day washout period between treatments. Blood samples were collected up to 144 hours post-dosing. Population PK modeling was performed using a two-compartment model with dual absorption kinetics (zero-order kinetics, followed by first-order kinetics with lag time). The model evaluation demonstrated good agreement between the observed and predicted concentrations, with no significant covariates identified. Simulation of steady-state trough concentrations indicated that daily doses of 3-4 mg of dispersible everolimus resulted in trough levels within the therapeutic range (5-15 ng/mL), whereas the 5 mg dose exceeded this range. These findings suggest that a daily dose of 3-4 mg is appropriate to maintain target trough concentrations in adults. This study supports the development of a dispersible everolimus formulation for adults with swallowing difficulties that can improve adherence and clinical outcomes. Further studies involving diverse patient populations are required to confirm these findings.