The soluble cytokine TNF-α is an important target for many therapeutic proteins used in the treatment of rheumatoid arthritis (RA). Biologics targeting TNF-α exert their pharmacological effects through binding and neutralizing this cytokine and preventing it from binding to its cell surface receptors. The magnitude of their pharmacological effects directly corresponds to the extent and duration of free TNF-α suppression. However, endogenous TNF-α is of low abundance and therefore it is quite challenging to assess the free TNF-α suppression experimentally. Here we have applied an experimental approach to bypass this difficulty by giving the studied animals rhTNF-α through SC infusion. This boosted TNF-α enabled quantification of TNF-α in plasma. Free rhTNF-α concentrations were measured after separation from the infliximab-rhTNF-α complex using Dynabeads Protein A. The interrelationship of infliximab and TNF-α was assessed with minimal physiologically-based pharmacokinetic (mPBPK) models for TNF-α and infliximab with a target-mediated drug disposition (TMDD) component. Knowledge of TNF-α PK allows reliable prediction of the free TNF-α suppression with either free or total TNF-α concentration profiles. The experimental and modeling approaches in the present study may aid in the development of next-generation TNF-α inhibitors with improved therapeutic effects.
- The American Society for Pharmacology and Experimental Therapeutics