114 Chapter 6 DISCUSSION For emicizumab in humans, this systematic review demonstrated a linear dose− concentration relationship with moderate inter-individual variability, with all ABR observations residing in the effectiveness plateau of this concentration−response relationship. Dose-concentration relationship With increasing doses of emicizumab, the primary PK parameters remained constant, while the exposure metrics exhibited a linear dose increase. These findings are in line with the results of the model by Retout et al., who showed a dose-proportional AUC increase due to constant clearance . Compared to the primary PK parameters of other therapeutic IgG4-based mAbs, the clearance of emicizumab was comparable (within 0.2−0.5 L/day), but distribution volumes were increased (10 vs 6 L) and, consequently, the reported half-life of emicizumab is longer . This higher volume of distribution is notable, indicating distribution to other compartments or binding of emicizumab, possibly to its targets in the blood circulation. In general, therapeutic mAbs demonstrate linear PK at high doses when the target-saturated concentration is achieved [39, 40], and this was observed already at doses of ≥ 0.1 mg/kg for emicizumab (Supplemental Figure SF2). The sources for variability of the PK parameters were explored in the two published population PK modelling studies, in which BW and neutralizing ADA against emicizumab were identified as influential covariates [24, 36]. A body-weight-based dosing regimen was justified, because including BW in the model reduced the inter-individual variability in CL/F from 56.4% to 30.0% and on V/F from 60.7% to 28.1% . Additionally, Retout et al. reported that age and albumin concentration were significantly correlated to primary PK parameters in their model. For age >30 years, bioavailability gradually decreased, and, for age >65 years, bioavailability strongly decreased (e.g., a 31% lower exposure for a PwHA aged 77 years than for PwHA aged 30 years), which is uncommon for therapeutic mAbs . Although the authors did not report a relationship with clinical response, PwHA older than 65 years may be more susceptible to lower emicizumab concentrations, potentially even reducing bleeding control in a small proportion of PwHA. A low albumin concentration of 33 g/L was associated with a 16% decrease in exposure . The PK variability across several studies was described in modelling studies before, but this review is the first to investigate variability across seven studies. We have reported slightly higher %CV for adults and adolescents compared to children. This finding is in line with the considerable influence of the covariate ‘age’ on exposure identified by Retout et al. . Therefore, we recommend to investigate the bioavailability and exposure in this patient subgroup (i.e., aged >30 years, especially >65 years) in future studies.