PBPK Modeling and Clinical Validation of Mirtazapine in the Vietnamese Population: Integration of Bioequivalence Data and Evaluation of the Impact of Physiological and Metabolic Variability

This study aims to develop and clinically validate a physiologically based pharmacokinetic (PBPK) model of mirtazapine in the Vietnamese population and to evaluate the influence of physiological characteristics, metabolic variability, and CYP2D6 genetic polymorphisms on drug exposure. The PBPK model will be developed using published physicochemical, metabolic, and clinical pharmacokinetic data, incorporating Vietnamese-specific CYP2D6 genetic and phenotypic distributions. Clinical validation will be performed by comparing PBPK-predicted plasma mirtazapine concentrations with observed concentrations obtained from healthy Vietnamese volunteers. Pharmacokinetic data from a bioequivalence (BE) study of mirtazapine will be used as supplementary data to support model validation. PBPK simulations will be conducted to investigate the effects of physiological and metabolic variability on mirtazapine exposure. The findings are expected to improve understanding of interindividual pharmacokinetic variability and provide a scientific foundation for future individualized mirtazapine therapy.

\*\*Inclusion Criteria:\*\* * Healthy male or female volunteers aged 18-55 years. * Body mass index (BMI) between 18 and 30 kg/m². * Non-smokers. * Vital signs within the protocol-defined acceptable ranges. * No clinically significant abnormalities in hematological and biochemical laboratory tests. * No clinically significant abnormalities on a 12-lead electrocardiogram (ECG). * Negative screening tests for HIV, hepatitis B, alcohol, and drugs of abuse. * Negative pregnancy test for female participants. * Considered healthy based on medical history, physical examination, and clinical assessment. * Able and willing to comply with study procedures and provide informed consent. \*\*Exclusion Criteria:\*\* * History of hypersensitivity to mirtazapine or any component of the study formulations. * History of hypotension or orthostatic hypotension. * Clinically significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, hematological, endocrine, neurological, psychiatric, or immune disorders. * Recent illness within two weeks before screening. * Use of prescription medications within two weeks or over-the-counter medications within one week before screening. * History of drug, alcohol, or tobacco dependence. * Blood donation or significant blood loss (greater than 450 mL) within 28 days before screening. * Gastrointestinal disorders or swallowing difficulties that may affect drug absorption. * Difficult venous access or inability to undergo repeated blood sampling. * Participation in another clinical study within one month before screening. * Pregnancy or breastfeeding. * Inability or unwillingness to understand and comply with the study protocol.