Dose Recommendation of Remimazolam Tosilate for General Anesthesia in Children and Adolescents: Synergistic Combination of PopPK and PBPK Approaches.

Background

Remimazolam tosilate is a novel, ultra-short-acting benzodiazepine. To address the unmet clinical need for safe and controllable general anesthetic options in children and adolescents, both top-down (i.e., population pharmacokinetics-PopPK) and bottom-up (i.e., physiologically based PK-PBPK) modeling approaches were combined to leverage their respective strengths for dose selection in children and adolescents aged 3-18 years.

Methods

Pooled PK data from adult studies were used to develop and verify the adult PopPK and PBPK models. The PopPK model included allometric scaling to describe body weight effects, while the PBPK modeling incorporated the age-dependent physiological and metabolic ontogeny. Potential covariates and intrinsic factors influencing remimazolam exposure were assessed. Both models were then applied to simulate PK and derive exposure metrics in 3-18-year-old children and adolescents. The predictions from both approaches were used to support pediatric dose selection using an adult-matching exposure approach.

Results

The PopPK and PBPK model simulations yielded consistent exposure predictions and converged on the same recommended dosing regimens for the pediatric population, providing mutual confirmation of model reliability. Both models indicated that the proposed regimens of remimazolam would achieve systemic exposures in children and adolescents (3-18 years) comparable to those in adults receiving an induction dose of 0.3 mg/kg followed by maintenance infusions of 1.0 or 3.0 mg/kg/h. Two pediatric dosing regimens were recommended: 1. Lower dose group: induction 0.2 mg/kg, initial maintenance 1.0 mg/kg/h, titratable as needed, with a maximum rate of 3.0 mg/kg/h (up to 4.0 mg/kg/h for individuals ≤ 30 kg). 2. Higher dose group: induction 0.3 mg/kg, initial maintenance 2.0 mg/kg/h, titratable as needed, with a maximum rate of 3.0 mg/kg/h (up to 4.0 mg/kg/h for individuals ≤ 30 kg). The model-informed dosing regimens have received regulatory approval from the Center for Drug Evaluation (CDE) in China and are currently being evaluated in an ongoing clinical trial.

Conclusions

The integrated PopPK-PBPK approach supports evidence-based dosing recommendations of remimazolam for general anesthesia in children and adolescents aged 3-18 years and provides a reference for dose selection in future clinical studies.