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Optimal use of a drug implies the correct dosage, with the lowest level just before the periodically administered medicine is taken (trough level) being sufficiently high to exert the full effect of the drug. On the other hand, peak levels and average levels should not exceed concentrations which are associated with increased toxicity. Therapeutic monitoring with measurement of trough levels at regular intervals is routinely carried out in the treatment with small molecules which have a narrow therapeutic window, for example ciclosporin. Surprisingly this therapeutic monitoring is not used at all to optimise treatment with monoclonal antibodies against biological targets. It is generally accepted that the clearance of a monoclonal antibody is quite predictable. For infliximab the terminal half-life is 9.5 days with a slow clearance rate (9.8 ml/h). The prolonged bioavailability of infliximab together with its high affinity for tumour necrosis factor (TNF (Ka = 1010/M) should result in effective and prolonged blockade of TNF with administration of 5 mg/kg every 8 weeks. However, the pharmacokinetics may not always be predictable. Clearance of infliximab is greatly increased in the presence of antibodies to infliximab (ATI). Moreover rapid clearance is also observed in a minority of patients without the presence of antibodies. The problem of immunogenicity of anti-TNF agents and the importance of achieving good trough levels was not well recognised in the pivotal trials in inflammatory bowel disease (IBD), and it was investigator-initiated cohort studies that pinpointed the problem.
In this issue of Gut, Seow et …