280. TRANSLATIONAL PHARMACOKINETIC-PHARMACODYNAMIC MODELING OF PRECLINICAL AND CLINICAL DATA OF THE TRIPLE REUPTAKE INHIBITOR JS1-1-01 TO DETERMINE THE RECOMMENDED PHASE II DOSE

Abstract Background JS1-1-01 is a novel dual-action mechanism antidepressant. The studies, in vitro and in vivo, have demonstrated that JS1-1-01 and its metabolite exhibit inhibitory effects on the uptake of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) in rat brain synaptosomes, and exhibit agonist effects on BDNF-TrkB/mTOR signal pathway. It is speculated that JS1-1-01 might exert a rapid antidepressant effect and significantly improve anhedonia in patients with depression. Aims & Objectives To enhance the success rate of clinical research and development, we proposed to employ translational research techniques and methodologies, integrating findings from non-clinical and healthy subject studies to conduct model development research. This approach aimed to establish dose recommendation for subsequent clinical investigations (NCT06259526). Method The comprehensive model development process was conducted incrementally as delineated below: (1) The plasma concentration-time profile in rats was modeled utilizing the pharmacokinetic (PK) model, followed by the computation of the total area under the curve (AUC) for each administered dose of the active substance; (2) The chronic unpredictable mild stress (CUMS) test in rats was characterized using the composite Emax model; (3) The plasma concentration-time profile in healthy subjects is modeled using the PK model, and the total AUC of the active substance at various dose levels is simulated (NCT05656274); (4) It is hypothesized that, given an equivalent AUC, patients with depression counld achieve a corresponding proportion of therapeutic efficacy. Results The ultimate population pharmacokinetic (PPK) model for JS1-1-01 and its metabolites in rats was characterized by a one-compartment framework, with the administered dose serving as a covariate influencing the absorption rate of JS1-1-01 and its metabolites. The typical pharmacokinetic parameters for the rat populations were determined, and the total AUC of active substances in rats administered doses of 0.625~5 mg/kg once daily were found to be 44.71~357.70 ng/mL·h, respectively. The baseline sugar preference in rats is measured at 0.904. In the CUMS model, the maximum response (Imax) is 16.9, with an IT50 of 390. For the compound JS1-1-01, the maximum effect (Emax) is 0.691, with an ET50 of 2.87 and a Hill coefficient of 2.09. It is anticipated that JS1-1-01 will exhibit antidepressant effects within 2-3 weeks. Administration of JS1-1-01 at a dosage of 5 mg/kg is expected to restore the sugar water preference in CUMS rats to levels comparable to those of the control group, which serves as the target effect. The population pharmacokinetic model for 40 healthy subjects is characterized by a two-compartment structure. Following oral administration, the drug undergoes sequential absorption into the central compartment, exhibiting both delayed and biphasic absorption phases (slow and fast). The likelihood of attaining a target area under the curve (AUC) of ≥ 357.7 ng/mL·h with daily doses of 50~200 mg, as determined through 1000 iterations of monte carlo simulations, is 31.0%, 90.3%, 99.3%, 100%, and 100%, respectively. Discussion & Conclusions A daily dose of 75~200 mg JS1-1-01 might achieve the target effect in patients with depression (>90%).