Comprehensive Parent-Metabolite PBPK/PD Modeling Insights Into Methotrexate Personalized Dosing Strategies in...

Area of Science:

• Pharmacology
• Rheumatology
• Computational Biology

Background:

• Rheumatoid arthritis (RA) poses a significant public health challenge, often necessitating treatment with low-dose methotrexate (MTX).
• Clinical response to MTX in RA patients exhibits considerable variability, indicating underlying pharmacokinetic and pharmacodynamic factors.
• Understanding these sources of variability is crucial for optimizing MTX therapy.

Purpose of the Study:

• To develop a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for methotrexate (MTX).
• To identify key drivers of pharmacokinetic (PK) variability and their relationship with clinical response in rheumatoid arthritis (RA).
• To explore potential dosing optimizations for MTX in RA patients, including those with renal insufficiency.

Main Methods:

• Development of a PBPK/PD model using PK-sim and Mobi software.
• Inclusion of MTX metabolism and transport pathways (e.g., AXO1, FPGS, GGH, RFC, MRP2) and excretion routes (renal, biliary).
• Simulation of various renal insufficiency populations and analysis of 23 MTX plasma concentration-time profiles.

Main Results:

• The PBPK model accurately predicted 97% of observed plasma concentrations within a two-fold range.
• Variability in renal clearance and MTX-metabolizing enzymes were identified as major contributors to PK variability.
• A quantitative relationship was established between MTX-polyglutamate 3 (MTX-PG3) and RA treatment response.

Conclusions:

• The developed PBPK/PD model effectively captures MTX pharmacokinetics and pharmacodynamics in RA.
• Renal function and specific enzyme activities are critical determinants of MTX response variability.
• The model serves as a valuable tool for guiding personalized MTX dose adjustments in RA management.