Local versus Systemic Anti-Tumour Necrosis Factor-α Effects of Adalimumab in Rheumatoid Arthritis

Abstract

The pharmacokinetic models that are applied to describe the disposition of therapeutic antibodies assume that the interaction between an antibody and its target takes place in the central compartment. However, an increasing number of therapeutic antibodies are directed towards soluble/mobile targets. A flawed conclusion can be reached if the pharmacokinetic and pharmacodynamic analysis assumes that the interaction between the therapeutic antibody and its target takes place in the central compartment. The objective of this study was to assess the relative importance of local versus systemic interactions between adalimumab and tumour necrosis factor (TNF)-α in rheumatoid arthritis (RA), identify localization of the site of adalimumab action and assess the efficacy of local (intra-articular) versus systemic adalimumab administration for treatment of RA. The clinical and preclinical data on adalimumab and TNFα disposition were analysed using a pharmacokinetic modelling and simulation approach. The disposition of adalimumab and TNFα and the interaction between them at the individual compartments (the synovial fluid of the affected joints, central and peripheral compartments) following different routes of adalimumab administration were studied. Outcomes of modelling and simulation using the pharmacokinetic model developed indicate that adalimumab can efficiently permeate from the diseased joints to the central circulation in RA patients. Permeability of TNFα, which is excessively secreted in the joints, is even higher than that of adalimumab. As a result, subcutaneous, intravenous and intra-articular administration of the clinically used dose of adalimumab (40 mg) exert similar effects on the time course of TNFα concentrations at different locations in the body and efficiently deplete the TNFα in all of the compartments for a prolonged period of time (8-10 weeks). At this dose, adalimumab exhibits predominantly systemic anti-TNFα effects at the central and peripheral compartments (∼93% of the overall effect) and the contribution of the local effects in the rheumatic joints is ∼7% for all of the studied routes, including the local intra-articular injections. The major pathway of TNFα elimination from the synovial fluid (∼77% for subcutaneous administration, and ∼72% for intravenous and intra-articular administration of adalimumab 40 mg) is interaction with adalimumab, which reaches the joints following local or systemic administration. The kinetics of adalimumab permeation to the synovial fluid (0.00422 L/h clearance of permeation) versus the rate of TNFα turnover in the affected joints (1.84 pmol/h synthesis rate and 0.877 h(-1) degradation rate constant) are apparently the major parameters that determine the time course of TNFα concentrations in the synovial fluid and the TNFα-neutralizing effects of adalimumab in RA patients. Outcomes of this study suggest that intra-articular administration of adalimumab is not preferable to subcutaneous or intravenous treatment. Local and systemic permeability, turnover and interactions between the drug and the target should be taken into account for optimization of the use of drugs acting on soluble targets (growth factors, interferons, interleukins, immunoglobulins, etc.).