Petra Jauslin 1, Henning Schmidt 1, Darius Schweinoch 1, Nikunjkumar Patel 2, Itay Perlstein 3, Avia Merenlender-Wagner 4, Anna Elgart 4, Rajendra Singh 2
1 IntiQuan AG (Basel, Switzerland), 2 Teva Branded Pharmaceutical Products R&D LLC (West Chester, USA), 3 Magic Wand Research LLC (Philadelphia, USA), 4 Teva Pharmaceutical Industries Ltd (Netanya, Israel)
Introduction/Objectives:
Olanzapine is an antipsychotic drug used in the treatment of schizophrenia with oral (PO) and intramuscular (IM) formulations currently marketed. TV-44749 is an investigational, once-monthly subcutaneous (SC) LAI olanzapine formulation designed to eliminate the risk of post-injection delirium/sedation syndrome (PDSS) observed with the currently available IM LAI formulation, while maintaining therapeutic efficacy. The objective of this work was to develop an integrated population pharmacokinetic (PopPK) model characterizing olanzapine pharmacokinetics (PK) across PO, IM IR (immediate release), and SC LAI formulations, identify relevant covariates, and predict exposure metrics for exposure-response analyses. Furthermore, the impact of switching between formulations, dosing irregularities and potential accelerated absorption scenarios was assessed through simulation.
Methods:
The data originated from two Phase 1 trials (TV44749-SAD-10154 and TV44749-NPC-10205) and one Phase 3 trial (TV44749-CNS-30096 / SOLARIS), comprising 805 participants overall. A PopPK model was developed using NONMEM version 7.5.1 (ICON plc, Gaithersburg, MD, USA) with the SAEM algorithm, following exploratory data evaluation. Covariates assessed included body weight, body mass index (BMI), age, height, sex, race, ethnicity, CYP1A2 metabolizer status, smoking status, and markers of hepatic and renal function.
Simulations of olanzapine exposure and dopamine D2 receptor occupancy (D2RO, a surrogate for efficacy) were performed based on individual post hoc parameter estimates (EBEs), as well as for a general patient population using estimated parameter variability and uncertainty, and covariate distributions as observed in the SOLARIS trial. Further simulation scenarios investigated the effect of switching between formulations, the impact of missed or delayed doses and of faster-than-expected SC absorption (50% and 100% increases of absorption rate).
Results:
Exploratory data analysis revealed dose-proportionality in exposure and two-compartment distribution with linear clearance across all formulations. IM IR administration exhibited faster absorption and distribution than PO dosing. SC LAI absorption demonstrated a bi-phasic pattern, with initial rapid absorption followed by a second delayed absorption phase. Phase 3 SC LAI data showed rapid trough accumulation during first three monthly doses followed by slower accumulation until achieving steady state at the 10th dose.
Absorption for PO and IM IR was characterized by first order (FO) processes, including a lag time for oral dosing. SC LAI absorption required a dual-pathway model consisting of an initial rapid FO absorption phase with a depot redistribution component to capture the time-dependency in trough dynamics, while the delayed phase used a transit compartment structure.
The final integrated PopPK model described olanzapine disposition with an apparent clearance of 16.4 L/h, a central distribution volume of 213 L, an intercompartmental clearance of 56.3 L/h, and a peripheral distribution volume of 673 L. Body weight, age, sex and smoking status were retained as covariates in the final model, of which sex and smoking status had the strongest influence on olanzapine clearance. These covariate effects were moderate in size (<30% deviation from typical parameters). No significant effects of renal or hepatic function-related covariates were detected. These findings were consistent with previously published covariate analyses for oral olanzapine [1]. Model diagnostics and visual predictive checks confirmed adequate model performance. Simulations showed that plasma concentrations and D2RO followed a parallel time course. D2RO exhibited reduced fluctuation and lower sensitivity to covariates than plasma exposure. Switching between PO and SC LAI formulations at steady state had minimal impact on exposure. Dosing irregularities of ±7 days also resulted in negligible exposure changes. Missed doses produced transient concentration decreases within the affected dosing interval, with full recovery at the next dose upon treatment resumption. Simulations of increasing the absorption rate by 100% showed an increase in maximum olanzapine plasma concentration by 15%. Conclusions: A two-compartment PopPK model successfully characterized olanzapine PK following SC, PO, and IM-IR administration. Sex and smoking status were identified as most relevant covariates with modest effects on exposure. The SC LAI formulation demonstrated robustness to formulation switching and minor impact of dosing irregularities. Even substantial increase in absorption rate had limited impact on overall exposure. These results support the once monthly SC LAI regimen. References: [1] Sun L, Mills R, Sadler BM, Rege B. Population Pharmacokinetics of Olanzapine and Samidorphan When Administered in Combination in Healthy Subjects and Patients With Schizophrenia. J Clin Pharmacol. 2021 Nov;61(11):1430-1441.
Reference: PAGE 34 (2026) Abstr 11919 [www.page-meeting.org/?abstract=11919]
Poster: Drug/Disease Modelling - CNS