(W1130-12-82) Mechanistic Modeling of Intramuscular Administration of Long-Acting Injectable Suspensions Accounting for Fibrosis at the Depot Site

Purpose: Antipsychotic drugs formulated as long-acting injectables (LAIs) significantly improve patient compliance compared to regimens that require daily oral administration¹. However, the clinical development of LAIs has proven challenging due to limited understanding of the tissue response to injected particles (e.g., inflammation, fibrosis formation) impacting in vivo performance. Mechanistic physiologically-based pharmacokinetic (PBPK) models could be valuable in establishing a link between in vitro formulation characteristics and in vivo performance while incorporating formulation interactions with the physiology. The purpose of this study was to use mechanistic PBPK modeling to delineate the in vivo performance of an LAI suspension, informed by in vitro data, and accounting for physiological responses at the injection site in humans. Aripiprazole (AR) was used as a model drug. For LAI formulation, AR is formulated as a prodrug AR-lauroxil (AR-L) which has very low solubility resulting in slow dissolution at the injection site. After injection into the muscle, AR-L slowly dissolves and is subsequently converted by esterases into AR before reaching the systemic circulation².

Methods: A simplified PBPK model that combines relevant properties of AR and AR-L was developed. This simplified model assumed quick AR-L to AR conversion, not impacting the rate of AR appearance in plasma. The systemic PK model was established based on AR characteristics, while dissolution at the depot site was based on AR-L properties, such as solubility. The physicochemical and biopharmaceutical properties of AR-L and AR were obtained from literature or public database^3,4 or predicted from their 2D molecular structures using ADMET Predictor® 10.3. In vitro formulation characterization (particle size distribution) of the drug product Aristada® was conducted. All simulations were performed using GastroPlus® 9.8.3. To describe AR systemic disposition and elimination, a three-compartment PK model was fitted to plasma concentration-time profiles after AR oral solution administration (15, 20, and 30 mg)⁵. The model was validated by predicting AR exposure following oral administration of AR solution (5 and 10 mg)⁵ and a tablet (5, 10, and 15 mg)⁴. The established systemic PK model was subsequently used to simulate AR systemic disposition after IM administration. The observed plasma concentration-time profile following AR IM solution administration in humans⁶ was used to inform the muscle-to-plasma partition coefficient. Subsequently, this established model was used to simulate AR exposure after IM administration of Aristada® (AR-L suspension) at three dose levels (150, 300, and 400 mg AR equivalent)⁷. The IM administration of solid material is known to cause an inflammatory response where an immune cell layer (ICL) is formed around the solid particles⁸. The ICL was included in the model with surface area (SA) estimated from the injected dose assuming a spherical depot shape. The time-dependent change in the ICL thickness was fitted to the observed PK data for the 400 mg eq IM Aristada® dose. The same kinetics of ICL thickness was used in simulation of the remaining IM Aristada® doses. Drug diffusion through the ICL was parameterized using AR-L LogP.

Results: The developed model adequately described the observed plasma profiles of AR following oral administration in humans with all the simulated Cmax and AUC_0-t values within ± 25% of the observed values (Table 1). The simulated Cmax and AUC_0-t for IM administration of AR solution were also within 25% of the observed values (Table 1). The observed plasma concentration-time profiles after IM administration of AR-L suspension showed a delay in the systemic appearance of AR (Figure 1), which was attributed to the formation of a dynamic ICL around the injected material. The ICL presents an additional barrier for the dissolved drug to diffuse through before reaching the systemic circulation, explaining the delayed Tmax. The model without the inclusion of ICL predicted an earlier Tmax than observed. The inclusion of an ICL in the model resulted in adequate predictions (prediction errors less than 50%) of the exposure parameters (Table 2) and of the shape of the plasma concentration-time profiles (Figure 1) for all three dose levels.

Conclusion: The drug absorption and PK profile of LAI suspensions are primarily affected by the kinetics of drug dissolution and the local inflammatory response at the injection site. The inflammatory response to the injected solid materials may result in formation of a fibrous band that traps the drug crystals at the injection site, resulting in delayed drug release and absorption. Utilizing SA calculation based on solid material and the same time-dependent change in ICL thickness across all dose levels resulted in reasonable predictions of AR PK profiles following IM administration of multiple strengths of the AR-L suspension. This shows the utility of PBPK model in mechanistically describing the in vivo performance of LAIs. Predicting the exposure of LAIs is challenging given the high variability and lack of available data to accurately parametrize the model, hence further studies are needed to validate and refine this approach.

References: 1. Correll, C. U. et al. Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview. CNS Drugs vol. 35 39–59 Preprint at https://doi.org/10.1007/s40263-020-00779-5 (2021).
2. Hard, M. L., Mills, R. J., Sadler, B. M., Turncliff, R. Z. & Citrome, L. Aripiprazole Lauroxil: Pharmacokinetic Profile of This Long-acting Injectable Antipsychotic in Persons With Schizophrenia. J Clin Psychopharmacol 37, 289–295 (2017).
3. Mihajlovic, T., Kachrimanis, K., Graovac, A., Djuric, Z. & Ibric, S. Improvement of Aripiprazole Solubility by Complexation with (2-hydroxy)propyl-β-cyclodextrin Using Spray Drying Technique. AAPS PharmSciTech 13, 623–631 (2012).
4. NDA Application 21436 - Abilify Clinical Pharmacology and Biopharmaceutics reviews; Parts 3 and 4, pp. 79-84
5. NDA Application 21713 - Abilify Clinical Pharmacology and Biopharmaceutics reviews; pp. 50-91
6. Boulton, D. W. et al. Pharmacokinetics and Tolerability of Intramuscular, Oral and Intravenous Aripiprazole in Healthy Subjects and in Patients with Schizophrenia Background Subjects and Methods. Clin Pharmacokinet vol. 47 (2008).
7. NDA Application 207533 - Aristada Clinical Pharmacology Review - pp.1-24 .
8. Ho, M. J. et al. Effect of Particle Size on In Vivo Performances of Long-acting Injectable Drug Suspension. Journal of Controlled Release 341, 533–547 (2022).

Acknowledgements: Disclaimer: This research was funded through the FDA Office of Generic Drugs; Contract # 75F40121C00133. The views expressed here do not reflect the official policies of the U.S. FDA or the Department of Health and Human Services, nor does any mention of trade names imply endorsement by the U.S. Government.

Table 1. Comparison of aripiprazole Cmax and AUC after oral and intramuscular administration of aripiprazole (AR)

Table 2. Comparison of aripiprazole Cmax and AUC0-t after intramuscular suspension administration of aripiprazole lauroxil (AR-L)

Figure 1. Observed (symbols) and predicted (line) AR plasma concentration vs time profile after IM administration of aripiprazole lauroxil (AR-L) suspension in humans. ICL: Immune Cell Layer.