Anouk Donners

15 General Introduction People with severe haemophilia A are monitored closely and receive prophylaxis early in life, while people with moderate and mild haemophilia A are monitored less often and mostly receive on-demand treatment. For dose monitoring, a minimal effective FVIII activity is the goal, and this goal differs between clinical situations. For instance, ≥1% of FVIII activity is required for prophylaxis, 30% for treating a mild bleed, or around 100% during surgery. High FVIII activity is not necessarily toxic but merely unattractive from a financial perspective, and high variability for FVIII products has been reported [4, 10]. Thus, monitoring for dose purposes is important to ensure sufficient efficacy. FVIII activity is currently measured with different clotting assays, mainly by the onestage clotting assay (OSA) or the chromogenic-substrate assay (CSA). These assays are routinely available in many clinical laboratories worldwide and are relatively fast and cheap to perform using an automated coagulation analyser. These assays demonstrate discrepancies in some cases, for instance, between the mild and moderate severity, between different FVIII-product types or between different laboratories [36]. Assay variability has been related to the use of different reagents, assay settings, assay interference (e.g., anti-drug antibodies [ADA] or non-factor products) and some lack of standardisation [36-38]. Ascertaining the FVIII activity is, however, critical in haemophilia A, particularly in the lower area of 0−6%. Measurement errors may worsen a person’s bleeding prognosis due to misdiagnosis of the severity classification, which results in postponed prophylaxis, or by suboptimal dosing of the FVIII products, which results in insufficient efficacy or financial “toxicity”. Monitoring of emicizumab Emicizumab is a so-called biopharmaceutical. The standard monitoring approach for biopharmaceuticals is TDM and the determination of anti-drug antibodies (ADA). The general purpose of monitoring is to guide treatment decisions to optimise treatment and cost-effectiveness. The dose selection of biopharmaceuticals is often set at the upper end of the dose–response curve, given the absence of a maximum tolerated dose. Moreover, the most important toxicity, immunogenicity, is not dose related [35, 39, 40]. For emicizumab specifically, its drug label does not mention laboratory monitoring or measurement of concentrations during treatment. However, guidelines on emicizumab therapy do recommend monitoring its concentration when suspecting ADAs [41]. Moreover, the monitoring of emicizumab might be useful in order for clinicians to recognise therapy non-adherence and for researchers to investigate its clinical pharmacology. Lastly, cost-efficient monitoring might be appealing when efficacy is maintained with lower doses of emicizumab, leading to healthcare savings and improved patient access [42]. Thus, the role of TDM for emicizumab is helpful in clinical support, research and potentially in cost-efficient dosing (see Figure 2). 1