Development of PBPK model for intra-articular injection in human: methotrexate solution and rheumatoid arthritis case study

Maxime Le Merdy,Jim Mullin,Viera Lukacova

doi:10.1007/s10928-021-09781-w

Abstract

A physiologically based model describing the dissolution, diffusion, and transfer of drug from the intra-articular (IA) space to the plasma, was developed for GastroPlus® v9.8. The model is subdivided into compartments representing the synovial fluid, synovium, and cartilage. The synovium is broken up into two sublayers. The intimal layer acts as a diffusion barrier between the synovial fluid and the subintimal layer. The subintimal layer of the synovium has fenestrated capillaries that allow the free drug to be transported into systemic circulation. The articular cartilage is broken up into 10 diffusion sublayers as it is much thicker than the synovium. The cartilage acts as a depot tissue for the drug to diffuse into from synovial fluid. At later times, the drug will diffuse from the cartilage back into synovial fluid once a portion of the dose enters systemic circulation. In this study, a listing of all relevant details and equations for the model is presented. Methotrexate was chosen as a case study to show the application and utility of the model, based on the availability of intravenous (IV), oral (PO) and IA administration data in patients presenting rheumatoid arthritis (RA) symptoms. Systemic disposition of methotrexate in RA patients was described by compartmental pharmacokinetic (PK) model with PK parameters extracted using the PKPlus™ module in GastroPlus®. The systemic PK parameters were validated by simulating PO administration of methotrexate before being used for simulation of IA administration. For methotrexate, the concentrations of drug in the synovial fluid and plasma were well described after adjustments of physiological parameters to account for RA disease state, and with certain assumptions about binding and diffusion. The results indicate that the model can correctly describe PK profiles resulting from administration in the IA space, however, additional cases studies will be required to evaluate ability of the model to scale between species and/or doses.

Highlights

The human knee is one of the largest and most complex joints in the body
Understanding of the knee joint physiology and its impact on active pharmaceutical ingredients (APIs) PK after intraarticular injection is critical for development of new APIs aiming to cure rheumatoid arthritis (RA) and other specific diseases affecting human joints
This research proposes the use of modeling and simulation to support drug product development for API administered intra-articularly

Summary

Introduction

The human knee is one of the largest and most complex joints in the body. It resides at the interface between the femur and the tibia. The inner membrane of the knee joint is the synovium, that is subdivided in the intima and subintimal layers. The intima is in direct contact with the joint cavity, itself filled with synovial fluid, a viscous, non-Newtonian fluid, whose principal role is to reduce the friction between the articular cartilages during movement [2]. To cure or reduce the symptoms of these pathologies, intra-articular (IA) injections in the synovial fluid that deliver high concentrations of active pharmaceutical ingredients (APIs) to the joint space are routinely

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