David Stepensky
Department of Pharmacology and School of Pharmacy, The Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Objectives: To estimate the inter-patient variability in the rheumatoid arthritis (RA) disease state and in the pharmacokinetics and pharmacodynamics of TNF-α-neutralizing antibodies. To estimate the resulting variability in the time course of local (intraarticular) vs. systemic concentrations of TNF-α and in the efficacy of RA treatment.
Methods: The available data from the scientific literature on the inter-patient variability of the RA disease state and the pharmacokinetics of TNF-α-neutralizing antibodies were analyzed using a target-mediated drug disposition (TMDD) model with three sites of antibody-TNF-α interaction (the synovial fluid of the affected joints, the central and peripheral compartments).
Results: The variability in the RA disease state and in subcutaneous absorption, distribution and elimination of the TNF-α-neutralizing antibodies was estimated. The time course of the TNF-α levels was affected to the highest extent by the disease state (i.e., baseline TNF-α secretion rates in the individual compartments) and the rate of antibody elimination. Variability of all the analyzed parameters had limited effect on the balance of systemic vs. local TNF-α-neutralizing effects of the studied antibodies due to their high permeability from the diseased joints to the central circulation in the RA patients.
Conclusions: Despite the extensive clinical use of TNF-α-neutralizing antibodies, the parameters that govern their efficiency in individual RA patients have not been identified. The effects of treatment on the local TNF-α levels in the affected joints and their correlation with the clinical markers of RA are largely unknown. Efficient RA treatment using TNF-α-neutralizing antibodies should take into account the inter-patient variability of local vs. systemic factors related to the disease state and the antibody pharmacokinetics. Similar analysis of inter-patient variability in local and systemic interactions between drugs and the target should be taken into account for other drugs acting on soluble targets (growth factors, interferons, interleukins, immunoglobulins, etc.).
References:
[1] Stepensky D. Local vs. systemic anti-TNF-alpha effects of adalimumab in rheumatoid arthritis: pharmacokinetic modeling analysis of interaction between a soluble target and a drug. Clin Pharmacokinet 2012, in press.
Reference: PAGE 21 (2012) Abstr 2334 [www.page-meeting.org/?abstract=2334]
Poster: Other Drug/Disease Modelling