143 DosEmi study protocol INTRODUCTION People with haemophilia A (PwHA) have a deficiency of coagulation factor VIII (FVIII) and present with spontaneous or provoked bleeds, predominantly into major joints leading to painful and chronic arthropathy [1, 2]. The cornerstone in the management of haemophilia A is still self-administration of FVIII concentrates by intravenous injections [3]. These injections are 2–7-times weekly to prevent bleeds (prophylaxis), or at the time of bleeding (on demand) when prophylaxis is unavailable. Prophylaxis with FVIII concentrates has effectively reduced the number of treated bleeds from an annual mean of 20−30 to 1−4 [4-7]. Additionally, anti-FVIII antibodies (known as inhibitors) render therapy with FVIII concentrates ineffective and develop in 30% of PwHA, who then require alternative, suboptimal therapies [8]. The first globally approved non-factor therapy is the bispecific, FVIII-mimicking antibody, emicizumab (Hemlibra®) [9]. Emicizumab became available for PwHA with severe haemophilia A in the Netherlands in July 2020. This novel drug promotes effective haemostasis, regardless of inhibitor status, achieving complete eradication of treated bleeds in around 80% of PwHA (n = 374) during the second 24-week interval of treatment [10]. More benefits of emicizumab are the subcutaneous and less frequent injections every 1, 2 or 4 weeks. Reported side-effects are thrombotic microangiopathy or thrombotic events when concomitantly using activated prothrombin complex concentrates in doses over 100IU/kg/day, which have not been observed since a change in guidelines for treatment of breakthrough bleeding [10]. Remaining side effects are the development of neutralizing or clearing anti-drug antibodies (ADA) against emicizumab (<1%) and injection-site reactions [10, 11]. Although many PwHA are candidate for prophylaxis with emicizumab, access is limited due to the financial impact on healthcare budgets. Emicizumab was approved with a loading dose of 3 mg/kg/week for four weeks and a maintenance dose of 1.5 mg/kg/week, 3 mg/kg/2 weeks or 6 mg/kg/4 weeks [12]. These dosing regimens were simulated in a pharmacometric approach, instead of a traditional dose-finding study, targeting a trough concentration (Ctrough) of 45 µg/mL [13]. Dosing according to drug label leads to mean concentrations of 55 µg/mL with 66% of observations between 40 and 70 µg/mL (SD of 15 µg/mL) [12, 14]. Additional real-world evidence from the Netherlands demonstrated that entire-vial dosing led to even higher concentrations of 63 µg/mL with 81% having concentrations >40 µg/mL [15]. In the meantime, the long-term bleed data from the phase III and IV studies were included in pharmacokinetic (PK) and pharmacodynamic (PD) modelling studies, and the minimal effective Ctrough was suggested at 30 µg/mL [14, 16-18]. Although this new target is substantially lower than the previous target, dosing regimens have not been adjusted. 8
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