125 Entire-vial dosing of emicizumab INTRODUCTION Emicizumab (Hemlibra®) prophylaxis provides effective bleeding prevention in persons with haemophilia A (PwHA) [1]. This humanized, bispecific FVIII-mimicking antibody was approved by the European and U.S. regulatory authorities for PwHA with and without FVIII inhibitors in 2018. The advantages of using emicizumab over the traditional factor VIII (FVIII) concentrates are subcutaneous administration instead of intravenous administration, longer dosing intervals with more continuous bleeding protection and no interference with FVIII inhibitors [2]. Emicizumab reduces the treatment burden for PwHA on prophylaxis, especially for those with FVIII inhibitors on bypassing agents (BPA) or with difficult venous access, and may enhance treatment adherence. Although many PwHA are candidates for emicizumab therapy, access to this therapy is limited due to the financial impact on healthcare budget of hospitals [3-5]. Emicizumab is available as injection vials for single use in four different vial sizes: 30 mg/1.0 mL, 60 mg/0.4 mL, 105 mg/0.7 mL and 150 mg/1.0 mL [6]. The maintenance dosage regimens, according to the drug label, are 1.5 mg/kg weekly, 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks (i.e., the dose per administration varies with body weight, but the dosing intervals are fixed). Given an individual’s weight, the dose is unlikely to exactly match the content of the vial size suggested by the online HEMLIBRA® calculator that is provided by the manufacturer, which often forces the prescribers to either overdose or discard the unused remainder of a vial. This introduces the risk of administration errors and leads to expensive drug waste, which are two topics of concern in the haemophilia community and society in general [7]. Entire-vial-based dosing could be used to tackle these two issues. While maintaining the mg/kg dose according to the registered label, the prescriber could extrapolate the dosing interval to the nearest vial size. For example, a PwHA with a body weight of 13 kg who receives 39 mg every 14 days according to the drug label (discarding 21 mg of a 60 mg/0.4mL-vial), could instead be given 60 mg every 21 days according to the entire-vial dosing. Until now, no studies on the efficacy outcomes of entire-vial dosing for PwHA in daily clinical practice were reported. Entire-vial dosing can be justified by the long elimination half-life of emicizumab (i.e., ~30 days), and the linear relationship across the three available dosing regimens suggests that alternative dosing combinations will result in similar plasma concentrations [7]. Furthermore, entire-vial dosing has been suggested to result in therapeutic plasma concentrations (~55 µg/mL) in two reports on pharmacokinetic modelling simulations [8, 9]. Therefore, we introduced entire-vial dosing to PwHA who receive emicizumab therapy in our clinic. The objective was to evaluate the efficacy of the entire-vial dosing of emicizumab by investigating real-world evidence of the plasma concentrations, bleeds and drug waste. 7
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