117 Systematic review on PK of emicizumab ABRs (excluding the median ABRs [28, 34, 35]) and excluded the studies with baseline imbalances [28, 35]. The ABR is not an entirely objective outcome parameter. Misinterpretation of bleeds might have occurred, as verification by the physician and complementary imaging were often missing. Subjective assessments, combined with follow-up periods of <12 months and small study sizes, may have affected the calculated ABRs. Moreover, clinically unstable disease leads to numerous (spontaneous) bleeds, especially in the first weeks of emicizumab treatment, leading to overestimation of ABRs in shorter studies [4346]. Recently, the analysis of pooled bleeding data from HAVEN 1−4 reported ABRs maintaining <1 in 24-week intervals and an increase in the proportion of PwHA without treated bleeds from 70.8% in the first 6 months to 80.2% after one year of emicizumab treatment [52]. Consequently, predicted ABRs may be overestimated in our model. The strength of this review was the large amount of information that has been summarized in tables and graphs. The novelty of this review was the critical appraisal by an independent research group, the dosing and monitoring considerations and the proposed role for TDM in relation to low concentrations and cost-effectiveness. This information may offer guidance in clinical decision-making and in future study designs assessing (cost-)effectiveness, safety and PK/PD modelling studies [53]. CONCLUSION This systematic review provided a comprehensive overview of PK and associated efficacy data for emicizumab in humans. Emicizumab demonstrated a clear linear dose− concentration profile with moderate inter-individual variability. The control of bleeds did not further improve above emicizumab concentrations of 30 µg/mL, potentially enabling lower dosing in a substantial proportion of PwHA. In conclusion, this review supports body-weight-based dosing, although individualized monitoring of emicizumab concentrations may allow for more cost-effective dosing. Author’s contribution AD designed the study, performed data management, conducted data curation, analysis, and validation, prepared the first draft of the manuscript, and implemented significant contribution from co-authors up to the final publication. Throughout the process, AD asked and implemented input and feedback from supervision team and co-authors, who performed critical review of the manuscript and provided significant contributions to the study. 6
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