(W1030-10-66) Model Development and Verification of Mechanistic Long-Acting Suspension-Based Injectable Model

Purpose: We present a mechanistic Physiologically Based Pharmacokinetic (PBPK) model of long-acting suspension-based injectables (LAI-Suspension). The model has been verified in vivo and can inform the design and analysis of clinical trials as well as the Virtual Bioequivalence (VBE) assessment of drug products. The model integrates prior physiological information on local injection sites (intramuscular and subcutaneous), in vitro information on active pharmaceutical ingredients and formulation parameters. The model was linked to a minimal physiologically based pharmacokinetic (mPBPK) model to simulate the clinical pharmacokinetics of several model drugs.

Methods: The model was written in C language. Inflammatory response to injection and subsequent change in local site volumes (local tissue, interstitial fluid, immune cell layer) and blood perfusions are considered. The model performance has been assessed with aripiprazole (ARP), triamcinolone acetonide (TAc) and olanzapine (OLA). The model input parameters are API’s physicochemical properties and binding information, steady-state volume of distribution (Vss), and clearance. Because of missing experimental data, diffusion and partition coefficients were parameterized using quantitative structure activity relationships (QSARs) models already implemented within the Simcyp Simulator V22 (Patel et al., 2022). Formulation-specific information was either collected from the literature or assumed. Local site volume change is modelled using an empirical equation due to a lack of experimental data or mechanistic models that describe the inflammatory responses. The equation used was V_d(t)=V_o+A_v x t x exp (-K x t) where V_d (t) is the volume of the depot/local site varying with time, Vo is initial local site volume, t is time and A_v, and K are constants. Parameters A_v and K were manually adjusted to recover the clinical data.
Case Study 1: Raoufinia et al., 2017 reported data of concentration vs time for single-dose administration of 400 mg Abilify Maintena ® after gluteal and deltoid administration in schizophrenic patients. The particle size data reported by Cai et al., 2018 was used to inform the model.
Case Study 2: ANDA 0901604 (USFDA, 2009) reports the pharmacokinetics of TAc (Kenalog 40) after 60 mg single-dose gluteal administration in healthy volunteers. Döppenschmitt et al., 1996 reports single dose pharmacokinetics of Kenalog 40 after 40 mg TAc single dose administration.
Case Study 3: Heres et al. (Heres et al., 2014) report single-dose pharmacokinetics of OLA equivalent to 405 mg and 300 mg. Particle size data were obtained from Paquette et al., 2014.

Results: In vivo disposition, after intravenous or oral administration was first simulated for the three drugs using the minimal PBPK and the ratio between observations and predictions were less than a factor two. Predictions of the kinetics of the three drugs after LAI-suspension injections were in close agreement with the observations as shown in Figure1.

Conclusion: The LAI-Suspension model predictions show good agreement with the clinical data. To model the drug absorption, formulation attributes of suspension products such as particle size data are taken into consideration and integrated with the physiology and local site dynamics. A current limitation of the model, due to the lack of experimental data on and mechanistic models of the local inflammation, is its empirical handling the local site volume changes. However, the model’s mechanistic basis of the formulation critical attributes should facilitate its parameterization from in vitro data and make it attractive for virtual bioequivalence assessment.

References: Cai, Q., He, L., Wang, S., Chu, W., Zhou, L., Pan, W., Zhang, L., Jiang, S., Ma, D., Liang, X., Gou, J., Yin, T., Zhang, Y., Tang, X., & He, H. (2018). Process control and in vitro/in vivo evaluation of aripiprazole sustained-release microcrystals for intramuscular injection. European Journal of Pharmaceutical Sciences, 125, 193-204. https://doi.org/https://doi.org/10.1016/j.ejps.2018.09.017
Döppenschmitt, S. A., Scheidel, B., Harrison, F., & Surmann, J. P. (1996). Simultaneous determination of triamcinolone acetonide and hydrocortisone in human plasma by high-performance liquid chromatography. J Chromatogr B Biomed Appl, 682(1), 79-88. https://doi.org/10.1016/0378-4347(96)00060-6
Heres, S., Kraemer, S., Bergstrom, R. F., & Detke, H. C. (2014). Pharmacokinetics of olanzapine long-acting injection: the clinical perspective. Int Clin Psychopharmacol, 29(6), 299-312. https://doi.org/10.1097/yic.0000000000000040
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Patel, N., Clarke, J. F., Salem, F., Abdulla, T., Martins, F., Arora, S., Tsakalozou, E., Hodgkinson, A., Arjmandi-Tash, O., Cristea, S., Ghosh, P., Alam, K., Raney, S. G., Jamei, M., & Polak, S. (2022). Multi-phase multi-layer mechanistic dermal absorption (MPML MechDermA) model to predict local and systemic exposure of drug products applied on skin. CPT Pharmacometrics Syst Pharmacol, 11(8), 1060-1084. https://doi.org/10.1002/psp4.12814
Raoufinia, A., Peters-Strickland, T., Nylander, A. G., Baker, R. A., Eramo, A., Jin, N., Bricmont, P., Repella, J., McQuade, R. D., Hertel, P., & Larsen, F. (2017). Aripiprazole Once-Monthly 400 mg: Comparison of Pharmacokinetics, Tolerability, and Safety of Deltoid Versus Gluteal Administration. Int J Neuropsychopharmacol, 20(4), 295-304. https://doi.org/10.1093/ijnp/pyw116
USFDA. (2009). Approval Package for: Application number ANDA 090164. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/anda/2009/090164Orig1s000.pdf

Acknowledgements: Other disclosure or conflict of interests- All the authors are employees of Certara UK Ltd (Simcyp Division).

Figure 1. Predicted and observed plasma concentration vs time profiles for (A) ARP-400 mg single dose gluteal administration, (B) ARP-400 mg single dose deltoid administration, (C)TAc-60 mg single dose gluteal administration (D) TAc-40 mg single dose gluteal administration (E) OLA-405 mg single dose gluteal administration and (F) OLA-300 mg single dose gluteal administration.