Category: Clinical Pharmacology
Purpose: The present study aims at elucidating the effect of injection site response on the rate of drug appearance in systemic circulation following intramuscular (i.m.) injection of Long-Acting Injectable (LAI) formulations. LAIs are recognized as a viable delivery approach for achieving stable therapeutic drug exposure over extended time. However, deposition of foreign materials results in injection site reactions (ISRs) that are not well characterized. The focus of this work is to model consequences of localized chronic inflammation in tissue on drug diffusion and exposure caused by prolonged therapy with long-acting formulations.
Methods: In this study, tissue response triggered by the parenteral injection is modeled as an inflammatory rim surrounding the formulation depot. This inflammation induced structure may serve as a physical barrier for diffusion of drugs and result in enhanced degradation of drug formulations [1, 2]. Immune cell layer (ICL) dynamic model developed in this study is based on work by Darville et al. , in which they determined local histopathological and immunological alterations generated by the IM (intramuscular) injection of paliperidone palmitate (PP)-LAI and polystyrene (PS) nano-/microsuspensions in rat. Our model accounts for drug diffusion through ICL with time-varying thickness and nonspecific tissue binding. Using the volume fractions of the formulation depot being infiltrated by inflammatory cell and absolute formulation depot cross-sectional areas data , we modeled the thickness of the infiltrated rim at any time (htICL) by a two-parameter bell shaped function.
Results: The dynamics of the infiltrated cell layer generated after a single intramuscular administration of paliperidone palmitate long-acting injectable in the rat is shown in Figure 1. Using the mathematical model obtained from rat data, parameter sensitivity analysis (PSA) was performed on both thickness model parameters to study their effect on systemic exposure of human subjects after receiving single paliperidone palmitate 50 mg eq. injection in the gluteal muscle. The baseline model was built using plasma concentration data in FDA NDA 22-264. . Figure 2(a) shows that Cmax increases by increasing the pre-exponential ICL growth term A(cm/hr), while it is decreasing by exponential ICL growth term, B (1/hr). Assuming the presence of ICL, Tmax is monotonically increasing when pre-exponential ICL growth term is increasing, however the effect of exponential ICL growth term on the Tmax is not monotonic (Figure 2(b)). No effect on AUC was observed during the PSA analysis.
Conclusion: Tissue response following administration of LAIs was modeled by an immune cell mediated diffusion barrier. Our model suggests that the dynamics of this layer is one of the key attributes in determining pharmacokinetics after administration of these formulations.
 Darville N, et al., Toxicologic Pathology 2016, Vol. 44(2)
 Doty A C, Doctoral Dissertation, University of Michigan 2015
 FDA NDA 22-264, Clinical Pharmacokinetics and Biopharmaceutics Review, Submission Dates: 03 February 2009
Viera Lukacova– Director– Simulation Sciences, Simulations Plus, Inc., Lancaster, California
Azar Shahraz– Lancaster, California
James Mullin– Team Leader Simulation Technologies, Simulations Plus Inc, Lancaster, California
Azar Shahraz– Senior Scientist, Simulations Plus, Inc., Lancaster, CA