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

Sep 29, 2026

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TV-44749 is a long-acting subcutaneous injectable formulation of olanzapine designed to provide controlled drug release across the dosing interval. Its formulation and SC administration aim to avoid post-injection delirium/sedation syndrome linked to intramuscular LAI olanzapine. Population pharmacokinetic modeling and simulation identify TV-44749 doses for a Phase 3 trial by matching exposure to approved oral dosing and achieving therapeutic D2 receptor occupancy (60%–80%). A double Weibull release model with two-compartment disposition supports dose selection.

LanguageEnglish

CategoryHealthcare

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Pages12

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Abstract

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Introduction

Original Article 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 The Journal of Clinical Pharmacology 2026, 66(1) e70144 © 2026 The Author(s). The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology. DOI: 10.1002/jcph.70144 Itay Perlstein, PhD 1 , Irina Cherniakov, PhD2 , Anna Elgart, PhDMBA2 , Roberto Gomeni, PhD2,3 , Dikla Gutman, PhD2 , Avia Merenlender Wagner, PhD2 , and Rajendra Singh, PhD4 Abstract 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 (Cmax, Cavg, 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). Keywords dose selection, long-acting injectable (LAI), olanzapine, population pharmacokinetics, subcutaneous olanzapine Introduction Schizophrenia is a chronic psychiatric disorder marked by a complex clinical presentation of positive and negative symptoms. 1,2 Its impact extends beyond primary symptoms, significantly affecting patients’ overall quality of life and longevity.3–5 Those living with schizophrenia have an increased risk of premature mortality, with life expectancy reduced by 10 to 25 years compared with the general population.3,4,6 Current treatment regimens for schizophrenia predominantly involve first- and second-generation oral antipsychotics. Despite their efficacy in managing symptoms, adherence to oral antipsychotics remains a significant clinical challenge, and nonadherence is a major modifiable risk factor for relapse.7,8 Consequently, many patients do not experience the full therapeutic benefit of antipsychotic therapy, leading to frequent relapses and exacerbations that often necessitate hospitalization.1 The use of long-acting injectable (LAI) antipsychotics is associated with improved treatment ad- herence, thereby reducing the risk of relapses and hospitalization.1 Since each relapse leads to further decline in mental and functional status, a key benefit of LAIs is the ability to maintain patients’ functionality and prevent additional decline. Olanzapine is one of 1 Magic Wand Research LLC, Philadelphia, PA, USA 2Teva Pharmaceutical Industries, Ltd., Netanya, Israel 3 PharmacoMetrica, La Fouillade, France 4Teva Branded Pharmaceutical Products R&D LLC, West Chester, PA, USA This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, whi

FAQs

What is TV-44749, and why was it developed?

TV-44749 is a long-acting subcutaneous injectable olanzapine using copolymer-based delivery technology. It is designed to control olanzapine release and reduce the risk of PDSS associated with intramuscular LAI olanzapine.

How were the TV-44749 doses selected for the Phase 3 trial?

Population pharmacokinetic modeling and simulation were used to select doses comparable to approved oral olanzapine exposures. The selected doses also targeted dopamine D2 receptor occupancy within 60%–80%.

What pharmacokinetic features were modeled for TV-44749?

The PK model used a double Weibull input function to represent two-phase release, followed by a two-compartment disposition model. Simulated steady-state PK parameters (Cmax, Cavg, and Ctrough) supported the final dose choices.

Sep 29, 2026

Uploaded by Aria