Clinical Information

Drug and target:

Adalimumab (ADL) is a monoclonal antibody (IgG1 kappa) which targets tumor necrosis factor (TNF)-alpha. TNF-alpha binds to TNF-alpha receptors, leading to the inflammatory response of autoimmune diseases. By binding to TNF-alpha, ADL can reduce the inflammatory response. Because TNF-alpha is also a part of the immune system that protects the body from infection, treatment with ADL may increase the risk of infections. Biosimilars have the same primary amino acid sequence as the reference or originator product. Therefore, ADL will be used to refer to both the reference product and the biosimilar products interchangeably. This test cannot distinguish between the reference product Humira and the ADL biosimilar products.

Indications:

Adalimumab is a subcutaneously administered. It is US Food and Drug Administration-approved for the treatment of multiple immune-mediated inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, Crohn’s disease (adults and pediatric patients ≥6 years), ulcerative colitis (adults), hidradenitis suppurativa, juvenile idiopathic arthritis (≥2 years), and non-infectious uveitis. Standard adult maintenance dosing is typically 40 mg subcutaneously every other week, with disease-specific induction regimens for inflammatory bowel disease and hidradenitis suppurativa. Dose escalation to weekly administration may be used in selected patients with inadequate clinical response.

Pharmacokinetics highlights:

Adalimumab has a half-life of approximately 2 weeks. It is usually given as a fixed dose (not weight-based). Peak serum concentrations are achieved approximately 5 days post-dose. Steady-state concentrations are achieved by 3 to 5 months of repeated dosing. Clearance of ADL can be influenced by similar factors as other anti-TNFs: high inflammatory burden, low albumin, and large body mass can increase clearance, while concurrent immunomodulators can reduce immunogenicity and clearance. There is considerable inter-patient variability.

Immunogenicity:

Around 30% of patients have no primary response to anti-TNF therapy, and up to 60% of initial responders experience secondary loss of response over time and require either drug dose-escalation or a switch to an alternative therapy in order to maintain response.(1) Reasons for primary loss of response may include disease processes mediated by proinflammatory molecules other than TNF. Secondary loss of response is associated with low serum albumin, high body-mass index, the degree of systemic inflammation and development of immunogenicity.(2,3) Antidrug antibody formation may increase drug clearance in treated patients or neutralize the drug effect, thereby potentially contributing to the loss of response. Antidrug antibodies (ADA) could also cause adverse events such as serum sickness and hypersensitivity reactions.(4) In clinical studies, the incidence of ADA formation varied with dose, concomitant immunosuppressants, and indication, and the presence of antibodies-to-adalimumab (ATA) was associated with lower serum ADL concentrations and, in some analyses, reduced clinical response. Concomitant methotrexate has been shown to reduce the frequency of ATA formation compared with ADL monotherapy. Measurement of ATA is dependent on assay sensitivity and drug tolerance, and comparisons should be made with caution. The clinical implications of ATA positivity should be interpreted in the context of drug concentrations, clinical response, and immunogenicity assay characteristics.

Evidence for therapeutic drug monitoring:

Adalimumab therapeutic drug monitoring (TDM) is supported by evidence for both reactive and proactive strategies. Reactive TDM is performed in the setting of loss of response or infusion reactions.(5) Reactive TDM is well validated to distinguish pharmacokinetic failure (low drug, absent antibodies) from immunogenicity (anti-drug antibodies), enabling rational dose escalation or switching and improving cost-effectiveness. Proactive TDM studies, involving routine measurement during maintenance stages of therapy, suggests benefits in reducing immunogenicity, maintaining remission, and optimizing long-term exposure, particularly early in therapy and in high-risk patients.(6,7)