Anouk Donners

115 Systematic review on PK of emicizumab Concentration−response relationship Our search did not yield individual patient data, making it unfeasible to use a complex model, such as repeated-time-to-event. However, the estimated EC50 of 1.47 µg/mL for treated bleeds was close to the previously reported values of 1.19 µg/mL [24] and 3.58 µg/mL [42] obtained by more sophisticated models, endorsing our model. The Ctrough,ss of 51.1 µg/mL obtained by the approved standard dosing regimens is 35-fold this EC50, which is abundant [13]. Our Emax model visualized the concentration−response relationship and revealed a clear effectiveness plateau from 30 µg/mL, beyond which no further increase in beneficial drug effect was achieved. All the bleeding rate observations of the included studies were well within this plateau, potentially enabling lower dosing for a substantial proportion of the PwHA. Unquestionably, setting other values for Emax and baseline ABRs would result in other predictions. A sensitivity analyses was performed (see Supplemental Table ST3) to show the impact of the ABR baseline and Emax assumptions on the estimates of EC50 and the ABRs for Ctrough,ss of 30 µg/mL and 50 µg/mL. In this regard the estimates remained approximately the same, indicating robustness. Also, the EC50 decreased fivefold when the ABRs (outliers) from HAVEN 1 were excluded from the model. We hypothesizes that many subjects from this study had long-term inhibitors and by definition had severe arthropathy, which is something to keep in mind for physicians. The ABR of treated joint bleeds was explored as well, because treated joint bleeds are generally better defined, reducing misclassification [43-46]. In the Emax model of treated joint bleeds, the effectiveness plateau was reached at even lower concentrations of 20 µg/mL. Dosing and monitoring considerations The question that remains is to what extent are we overdosing our PwHA? Based on our Emax models, a Ctrough,ss of 30 and 50 µg/mL would result in ABRs of treated bleeds of 2.4 and 1.9, respectively (RRRs of 91% and 93%, respectively) and ABRs of treated joint bleeds of 1.1 and 1.0, respectively (RRRs of 94.9% and 95.4%, respectively). Are the theoretic ABR differences of 0.5 and 0.1 clinically relevant while the RRRs remain essentially equal? Understandably, manufacturers design dosing regimens without laboratory monitoring, because this is user-friendly and robust. Moderate inter-individual variability in PK without monitoring necessitates higher dosing to guarantee efficacy for all users. In combination with an absence of toxicity at high drug concentrations, which is the case for most therapeutic mAbs, this makes overdosing clinically not problematic. Nonetheless, concerns were expressed by Hooimeijer et al., who reported joint pain episodes in a PwHA at high emicizumab concentrations of 90 µg/mL, which resolved after dose reduction to concentrations of approximately 30 µg/mL [33]. Furthermore, when drugs are costly (the wholesale acquisition cost of emicizumab is approximately US$482,000 for the first year of treatment and US$448,000 for following years), monitoring and subsequent dose reduction may lead to substantial savings in health care [47]. The weighted overall variability of the Ctrough,ss was 32%, which is common 6