Anouk Donners

182 Chapter 10 demonstrated dose−linear PK and a moderate (32%) inter-individual variability of trough concentrations (Ctrough). 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. Therefore, the study supported body-weight-based dosing but suggested individualized monitoring of the emicizumab concentrations to dose more cost-efficiently. The LC-MS/MS method (Chapter 5) and PK knowledge (Chapter 6) were then used to conduct a single-center, observational study, described in Chapter 7. Emicizumab is dosed on body-weight at 7-, 14- or 28-day intervals which often mismatches the vial content. To avoid drug waste, PwHA at our clinic received emicizumab doses of entire vials, but with variable intervals. Real-world evidence on concentrations, bleeds and drug waste was collected and evaluated. A total of 112 individuals (94% severe phenotype and 9% FVIII-inhibitor positive) were followed for a year before and a year during emicizumab therapy. Therapeutic concentrations of emicizumab were observed. The annualized treated bleeds reduced significantly from 3.6 before to 0.8 during emicizumab. Drug waste was reduced by 9%. The entire-vial dosing of emicizumab seemed an attractive treatment option for PwHA leading to therapeutic concentrations, good bleeding control and drug waste avoidance. Dosing according to label resulted in Ctrough of 55 µg/mL, while moderate variability and an effective Ctrough of 30 µg/mL have been reported. This statement in combination with the three thesis Chapters 5, 6 and 7 formed the groundwork for a study protocol described in Chapter 8. The DosEmi study has a phase IV, multicenter, open-label, crossover design. The study will evaluate noninferiority of bleed control of ≥6 months on conventional dosing in comparison to ≥6 months on dose intervention. The dose intervention consists of reducing the dose to target a Ctrough of 30 µg/mL using individual-PK parameters. The DosEmi study was approved by the local Medical Ethics Review Committee and is currently including participants to further investigate the findings from this thesis. Discussion and conclusion In Chapter 9 general discussion, two themes further built upon the results from the thesis. The first theme included four potential future applications for monitoring FVIII concentrations in haemophilia A using LC-MS/MS analysis: multiplexing, discrepant FVIII activity, neonatal screening and dried-blood-spot sampling. In the second theme, a framework for cost-efficient dosing strategies of biopharmaceuticals was provided from idea to clinical-practice implementation. This thesis added knowledge to the optimisation of monitoring FVIII and emicizumab in PwHA by addressing some issues while simultaneously raising others, and now future researchers, pharmacists and clinicians must further build on the findings of this thesis.