Anouk Donners

102 Chapter 6 ABSTRACT Introduction Emicizumab is an effective, new treatment option for people with haemophilia A (PwHA). The approved dosing regimens are based on body weight without the necessity for laboratory monitoring. This assumes a clear dose-concentration-response relationship, with acceptable variability due to factors other than body weight. To investigate this assumption, a systematic review on the pharmacokinetics (PK) and associated efficacy of emicizumab in humans was conducted. Methods The databases Embase, Pubmed and CENTRAL were systematically searched up to November 2020 to identify studies on PK data of emicizumab in humans. Data on the study, population, PK and efficacy (annualized bleeding rate of treated [joint] bleeds) were extracted and synthesized, and exposure effects modelling was performed using non-linear least squares regression in a maximum effect (Emax) model. Results The 15 studies included reported data for 140 volunteers and 467 PwHA, including children (0 to <12 year), adolescents and adults (≥12 year), both with and without factor VIII (FVIII) inhibitors. Emicizumab demonstrated dose-linear PK. The inter-individual variability of trough concentrations was moderate (32%) and similar across various subgroups, such as FVIII inhibitor status, age group and dosing interval. 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. Conclusion This review supports body-weight-based dosing, although individualized monitoring of emicizumab concentrations may allow for more cost-effective dosing.