(T1030-12-67) Multiphysics Simulations and Pharmacokinetic Modeling of Long-Acting Injectable Delivery Systems

Purpose: Chronic disease prevalence globally demands development of effective treatment regimens. Commonly used oral regimens are often complex, high dose, and sometimes given multiple times daily, which complicates a patient’s ability to adhere to drug regimens. Poor adherence can lead to disease progression as well as drug resistance. Long-acting injectables, or LAI, can improve adherence by reducing the frequency of administration as well as simplifying drug regimens. However, translation of these products from the bench to the clinic is stilted. One reason for this is the lack of understanding regarding absorption rate kinetics at the injection site (i.e. subcutaneous), and how LAI formulations interact with human physiology to impact drug plasma concentration profiles.

Methods: My project seeks to address this gap in knowledge by developing a multiscale, multiphysics computational framework to understand the mechanisms behind: a) local drug dissolution and release from injection sites, b) physiological impacts on absorption rate kinetics, and c) resulting drug pharmacokinetic profiles. Our previously developed Computational Fluid Dynamics (CFD) subcutaneous model was adapted from lymphatic (for mAb) to capillary (for small molecules) absorption. In addition, it was expanded to include a dissolution model to simulate the effect of nanosuspension formulation critical quality attributes (CQA, such as particle size/dissolution rates, drug solubility, membrane permeability, etc) and injection site physiology on absorption rate kinetics. The kinetics obtained from this model were implemented into a compartmental pharmacokinetic model to simulate drug plasma concentration profiles.

Results: Two drugs were used for simulations of solution (methotrexate, MTX) and suspension (medroxyprogesterone acetate, MPA) subcutaneous drug administration. A sensitivity analysis for MTX showed greater impact of membrane permeability on small molecule absorption rates than other drug or physiological vessel properties. Pharmacokinetic analysis also validated the membrane permeability value obtained against different doses. A sensitivity analysis for dissolution rates and solubility of MPA showed a varying impact on the combination of these two variables on absorption rates, indicating that consideration of both formulation parameters can greatly change local and systemic concentration profiles. Pharmacokinetic analysis showed that this framework can also demonstrate how drug dissolution rates may be affected at different sites of administration for MPA (ab/thigh vs. arm).

Conclusion: Overall, our modeling framework is versatile in determining the effect of many distinct but integral formulation, drug, and physiological parameters on absorption rates and systemic pharmacokinetics. By implementing this framework, we can better understand physical mechanisms of formulation on absorption to better inform LAI development for subcutaneous administration.

References: 1. Zheng, F., Hou, P., Corpstein, C. D., Xing, L. & Li, T. Multiphysics Modeling and Simulation of Subcutaneous Injection and Absorption of Biotherapeutics: Model Development. Pharmaceutical Research 38, 607–624 (2021).
2. Hou, P., Zheng, F., Corpstein, C. D., Xing, L. & Li, T. Multiphysics Modeling and Simulation of Subcutaneous Injection and Absorption of Biotherapeutics: Sensitivity Analysis. Pharmaceutical Research 38, 1011–1030 (2021).
3. Zheng, F., Hou, P., Corpstein, C. D., Park, K. & Li, T. Multiscale pharmacokinetic modeling of systemic exposure of subcutaneously injected biotherapeutics. Journal of Controlled Release 337, 407–416 (2021).
4. Pichlmeier, U. & Heuer, K.-U. Subcutaneous administration of methotrexate with a prefilled autoinjector pen results in a higher relative bioavailability compared with oral administration of methotrexate. Clinical and experimental rheumatology 32, 563–571 (2014).Bao Q, Zou Y, Wang Y, Choi S, Burgess DJ. Impact of Formulation Parameters on In Vitro Release from Long-Acting Injectable Suspensions. AAPS J. 2021 Mar 11;23(2):42. doi: 10.1208/s12248-021-00566-0. PMID: 33709196; PMCID: PMC8684597.
5. Bao Q, Zou Y, Wang Y, Choi S, Burgess DJ. Impact of Formulation Parameters on In Vitro Release from Long-Acting Injectable Suspensions. AAPS J. 2021 Mar 11;23(2):42. doi: 10.1208/s12248-021-00566-0. PMID: 33709196; PMCID: PMC8684597.
6. Depo-SubQ Provera – medroxyprogesterone acetate package insert.
7. Halpern V, Combes SL, Dorflinger LJ, Weiner DH, Archer DF. Pharmacokinetics of subcutaneous depot medroxyprogesterone acetate injected in the upper arm. Contraception. 2014 Jan;89(1):31-5. doi: 10.1016/j.contraception.2013.07.002. Epub 2013 Jul 12. PMID: 23993431.

Acknowledgements:

Funding: Center for Pharmaceutical Processing Research (CPPR)


Fig. 1: Multiscale Model Framework for Subcutaneous Drug Absorption. Our local, first-principles model integrates physics fields (tissue displacement, interstitial fluid velocity, and mass transport of drug)1-3 to determine how properties of drug (e.g. permeability, solubility, dissolution) and local physiology (e.g. blood pressure, vessel tissue area) affect systemic plasma drug concentrations.


Fig. 2: Simulated Pharmacokinetic Profiles for Methotrexate (MTX) Solution Administration. (Left) Sensitivity analysis for the effect of membrane permeability (Pd) for MTX (dose = 7.5 mg) on absorption rates (Ka) and subsequent effects on plasma drug concentrations. (Right) Simulated plasma drug concentrations for different doses of methotrexate4 using a Ka value of 0.295/h (Pd=3.5e-5 cm/s).


Fig. 3: Simulated Pharmacokinetic Profiles for Medroxyprogesterone Acetate (MPA) Suspension Administration. (Solid lines) Sensitivity analysis for varying values of dissolution rates (Kd) and experimental solubility5 (Cs) on absorption rates (Ka) and subsequent simulated plasma concentration profiles of an MPA suspension. (Shapes) Experimental pharmacokinetic profiles for typical (ab/thigh)6 and arm7 administration of Depo-Provera SubQ.