Population Pharmacokinetic Model‐Based Dose Selection of Extended‐Release Injectable Olanzapine (TV‐44749) for Subcutaneous Use in Phase 3 Clinical Trial in Adults with Schizophrenia

TV-44749 is a long-acting subcutaneous (SC) injectable olanzapine based on a novel copolymer drug delivery technology ensuring controlled olanzapine release over the dosing interval. TV-44749's formulation and SC route of administration aim to eliminate the causes of post-injection delirium/sedation syndrome (PDSS) that may occur with the intramuscular LAI olanzapine formulation. The main objective of this analysis was to utilize a population pharmacokinetic (PPK) modeling and simulation approach to select TV-44749 doses for a Phase 3 clinical trial that are comparable to the oral olanzapine approved doses and achieve dopamine D2 receptor occupancy (D2RO) within the therapeutic range. The PPK model was developed using data from a Phase 1 study in healthy participants and patients with schizophrenia or schizoaffective disorder. The Phase 1 study consisted of an oral olanzapine period followed by a washout and then single or multiple doses of TV-44749. The PK model was characterized by a double Weibull input function representing a two-phase drug release: an initial rapid release of a fraction of the dose, followed by a delayed and sustained release of a second fraction with two-compartment disposition model. The predicted steady-state pharmacokinetic parameters (C_max, C_avg, and C_trough) of once-monthly TV-44749 doses of 318, 425, and 531 mg were comparable to daily oral doses of 10, 15, and 20 mg, respectively. The exposure values resulted in simulated D2RO levels within the recommended range (60%-80%) and were therefore selected for the Phase 3 trial of TV-44749 (SOLARIS; NCT05693935).