Anouk Donners

135 Entire-vial dosing of emicizumab Drug waste Compared to label-based dosing, the total drug waste avoided was 28,533 mg of emicizumab in the period studied, corresponding to a mean annualized drug waste of ~260 mg per adult/adolescent or ~200 mg per child. The mean relative drug waste was 9% per individual with a minimum of 0% and a maximum of 40%. The 18 individuals with a drug waste of ≥15% had a median body weight of 16 (13–23) kg, and median age of 4 (IQR 2–7) years. These individuals (n = 8) were mostly prescribed dosing intervals of 21 days for entire-vial dosing. DISCUSSION We demonstrated the efficacy of entire-vial dosing of emicizumab in 112 PwHA during 96 person-years. Real-world evidence demonstrated therapeutic plasma concentrations and good bleeding control. The drug waste was reduced by 9% after introduction of entire-vial dosing in our clinic, which was equal to a mean annualized drug waste of ~260 mg per adult per year. When emicizumab is dosed with 6mg/kg every 4 weeks according to the drug label, the mean trough concentration is 38 µg/mL, midway 54 µg/mL and peak 67 µg/mL, while weekly-dosing intervals result in almost constant concentrations varying between 51 and 55 µg/mL [6]. Due to the retrospective study design, the concentrations could not be classified as trough, midway or peak concentrations. Nevertheless, the observed median concentration was 63 µg/mL, and was 69 µg/mL in adults/adolescents, which indicates higher concentrations in this study than in the drug label [6]. Possibly entire vial dosing may have resulted in higher concentrations due to overfilling of vials. Indeed, regulators have recommended overfilling vials of liquid drug products because it may be difficult or impossible to remove 100% of the content from a vial. Regulators are concerned that manufacturers overfill vials without appropriate justification, which is not clear or made public for emicizumab vials [15]. Thus, the entire-vial dosing may have led to the administration of overfilled vials in our cohort, explaining the higher concentrations achieved in comparison to concentrations from the registration studies, and we recommend to measure a concentration when applying the entire-vial dosing strategy. The within-individual variability observed (15% and 22%) is in line with previous studies [16] and may have originated from the undefined sampling times (trough-peak fluctuations) or/and (not reported) adherence issues. Based on clinical observation and emicizumab concentrations, the presence of ADAs against emicizumab was not suspected in our cohort. This is in concordance with the low reported immunogenicity risk [17] and the current guidelines recommending emicizumab’s concentration measurement in the absence of ADA-detection assays [18]. 7