Category: Clinical Pharmacology
Purpose: Intra-articular injections are widely used to treat inflammatory joint issues like rheumatoid and osteoarthritis. Steroids, pain relievers, immune system suppressants, and hyaluronic acid are typical therapies that improve joint function and/or reduce pain and inflammation. Understanding local concentrations in intra-articular tissues and fluids such as cartilage, synovial membrane, and synovial fluid is valuable to predict potential pharmacodynamic effects and efficacy of injection products and describe the effect of disease states on the disposition of drug. Therefore, a PBPK model was developed that incorporates solubility, dissolution, particle size distribution, tissue or protein binding, diffusion, and uptake into systemic circulation of active pharmaceutical ingredients (APIs) after injection in the knee joint capsule. Methotrexate (MTX) and triamcinolone acetonide (TCA) simulation studies were conducted to test the new model and determine what future improvements are necessary. This first step will accelerate the development of additional elbow joint models and facilitate disease state predictions.
Methods: Intra-articular PBPK model was implemented in GastroPlus® Version 9.7 using a system of coupled ordinary and partial differential equations. The model diagram is displayed in Figure 1. Drug injected to the synovial fluid dissolves based on a mechanistic dissolution model or prescribed dissolution profile. Once drug is dissolved in synovial fluid, it diffuses either through the intimal and subintimal membrane into systemic circulation or into the cartilage tissue. The subintimal and intimal membrane of the synovium are each modeled as a single compartment due to the thin dimension compared to the cartilage. The cartilage tissue is split into ten (10) subcompartments and the method of lines is used to calculate the diffusion in the cartilage tissue. Diffusive flux equality boundary conditions are assumed between the synovial fluid and synovial membrane and cartilage. Initial conditions consist of the dose, dose volume, particle size distribution, and/or prescribed dissolution profile of the API depending on the injected dosage form. The model was parameterized for mouse, rat, monkey, dog and human from physical measurements, structure activity relationships (SAR), or theoretical models for: pH, viscosity, fraction unbound, diffusivity, and volume of synovial fluid; and volume, surface area, diffusivity, fraction unbound, and blood flow in intimal and subintimal membrane as well as articular cartilage. Model validation was performed with PK data for IV, PO, and intra-articular administration of MTX and TCA [2,3,4,5]. A two compartment PK model was used to describe the systemic distribution of MTX and TCA.
Results: The MTX model was built assuming a disease arthritic state with increased synovial volume and membrane area. Diffusivities in synovial fluid, synovium and cartilage were initially predicted from logP based on tissue diffusivities in the oral cavity and subsequently adjusted (increased 1000-fold for synovial fluid and synovium and 100-fold for cartilage) to match the observed PK data. The final adjusted diffusivities came close to the diffusivity of MTX in water. The initial estimate for fraction unbound in synovium (Fu) was 66% based on prediction from oral cavity tissues and was adjusted to 90% to fit the synovial and plasma concentrations as shown in Figure 2. The TCA model utilized two methods in order to predict the PK of the 40 mg Intra-articular injection. The first method assumed slow diffusion in synovial fluid as predicted by the Stokes-Einstein equation from synovial fluid viscosity. The second method assumed that the diffusivity of TCA in synovial fluid is equal to water and the limiting step was slow dissolution rate due to particle agglomeration. TCA predictions are shown in Figure 3.
Conclusion: The intraarticular model accounts for all relevant physiologic parameters for various preclinical species and human. It utilizes all available literature for pH, volumes, surface areas, and flows for each tissue compartment. Model validation was performed using data for MTX and TCA. MTX required diffusion coefficients similar to water in all compartments and a fitted Fu in synovial fluid and membrane to match the Cp-time data, while the TCA model required either the Stokes-Einstein viscosity-based model to predict slow diffusion or the assumption of particle agglomeration resulting in slow dissolution. Future work will aim to improve Fu and diffusivity predictions, build models for elbow joints, and provide disease state models.
James Mullin– Team Leader Simulation Technologies, Simulations Plus Inc, Lancaster, California
Maxime Le Merdy– Lancaster, California
Viera Lukacova– Director– Simulation Sciences, Simulations Plus, Inc., Lancaster, California
Michael Bolger– Chief Scientist, Simulations Plus, Inc., Lancaster, California