2026 ECNP Congress

PS02-2247

Joint population pharmacokinetic model of olanzapine following oral, intramuscular, and subcutaneous administration to support TV-44749 dose recommendations and switching strategies

Avia Merenlender Wagner — N. Patel, I. Perlstein, A. Elgart, R. Singh · Teva Pharmaceutical Industries Ltd., Clinical Pharmacology & Pharmacometrics- Specialty Clinical Development, Netanya, Israel

2026 ECNP Congress

Background

Olanzapine (OLZ) is a second-generation antipsychotic available in oral, intramuscular (IM) immediate-release (IR), and IM long-acting injectable (LAI) formulations. Long-term adherence to oral antipsychotics in schizophrenia is challenging and can be improved with LAIs. Due to post-injection syndrome risk and post-injection monitoring requirements, IM LAI OLZ pamoate clinical use is limited. TV-44749 is an investigational, subcutaneous (SC) LAI OLZ designed to provide sustained efficacy over monthly dosing and avoid post-injection syndrome risk. Pharmacokinetics (PK) of TV-44749 versus other OLZ formulations were characterised using population PK (popPK) modelling to evaluate covariate effects, dosing, and switching strategies.

Methods

PK data from Phase 1 (SAD-10154 [oral OLZ, TV-44749]; NPC-10205 [IM IR OLZ, TV-44749]) and Phase 3 SOLARIS (NCT05693935; TV-44749 318, 425, and 531 mg) trials were used to build a joint popPK model for oral OLZ, IM IR OLZ, and TV-44749. Absorption processes for each route were modelled stepwise. Covariates included age, sex, body weight, and smoking status. The model used a standard compartmental nonlinear mixed-effects approach. PK exposure simulations were performed using individual parameter estimates and population variability. Switching between formulations was simulated.

Results

Analysis included 805 participants and 15,098 PK samples (oral, 14.9%; IM IR, 11.5%; TV-44749, 73.6%). Mean (SD) age was 44.5 (11.4) years; 73.4% were male, and 74.7% were smokers. Following TV-44749 administration, Day 1 OLZ exposure was comparable to oral dosing and was sustained over the monthly dosing interval, consistent with a long apparent half-life (TV-44749, 46.5 days; oral, 1.6 days). Estimates of apparent clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 393 L/d, 213 L, 1350 L/d, and 673 L, respectively. Simulations consistently demonstrated dose-proportional increases in TV-44749 exposure. Average plasma concentration (Cavg) reached >80% of steady state (SS) by the third monthly dose across dose levels, with only minimal incremental increases thereafter until reaching SS at the tenth dose. Exposure following TV-44749 administration was within oral OLZ variability range from first dose to SS. Sex and smoking were the most influential covariates. Simulations of switching between TV-44749 and oral OLZ showed similar PK variability, with Cavg and peak plasma concentration (Cmax) within 25% of SS oral levels. Delayed dosing (≤1 week) had minimal impact; a missed dose affected only the dosing interval, with recovery after re-dosing. No dose dumping was observed; simulations showed that a hypothetical 100% increase in absorption rate would result in modestly increased Cmax of approximately 15%.

Conclusions

A comprehensive popPK model incorporating oral, IM, and SC OLZ described linear, dose-proportional PK with estimated apparent clearance and volume parameters for TV-44749, comparable with prior reports. Covariate analysis showed that sex and smoking significantly affected PK, consistent with known effects for oral OLZ and not requiring dose adjustment. Switching between TV-44749 and oral/IM formulations maintained exposure. Limited impact of delayed dosing indicates robustness against dosing irregularities. A simulated 100% increase in the rapid absorption rate of TV-44749 only modestly increased Cmax, further supporting the robust prolonged-release characteristics of TV-44749.

References

No references