Anouk Donners

116 Chapter 6 for therapeutic mAbs. Notably, individual Ctrough,ss ranged widely from 2.8 to 148 µg/mL [18]. No specific loss of efficacy nor side effects for these extreme individual cases were described. As more studies presented subjects with plasma concentrations <20 µg/mL (Supplemental Table ST2), we propose a beneficial role for Therapeutic Drug Monitoring to increase the dose to an efficacious concentration. In addition, we recommend to conduct a prospective, individual PK-guided dosing study to target an efficacious trough concentration of 30 µg/mL and to collect data on both inter-individual variability and inter-occasion variability in the real world setting to optimize efficacy, safety and costeffectiveness of emicizumab treatment. Laboratory monitoring with PD biomarkers has been unsuccessful, and functional assays should be interpreted with caution and as relative indications of the procoagulant potential [34, 48]. Until proper functional tests become available, the emicizumab concentration appears to be the best predictor for bleeding risk [24]. The concentration is not routinely monitored in clinical practice, although monitoring may be useful for research purposes, to check adherence, or in case of suspected neutralizing ADA against emicizumab [49]. The emicizumab concentration was measured in PK samples during phase I−III clinical studies using an enzyme-linked immunosorbent assay (ELISA) and during phase IV studies using a modified, calibrated one-stage clotting assay (OSA). Unfortunately, Roche has not provided access to the ELISA while the OSA is available only at specialized laboratories, as it needs to be calibrated by a standardized kit of two reference values [50]. An assay capable of measuring emicizumab concentrations in human plasma on routinely available platforms, such as liquid chromatographytandem mass spectrometry (LC-MS/MS), would be valuable. An LC-MS/MS method for the quantification of emicizumab has been developed and validated at the University Medical Center Utrecht [51]. Limitations & Strengths This systematic review was limited by the number of available studies, the inclusion of funded studies, a heterogeneous population, limited study sizes and lack of studies with a blinded, placebo-controlled, head-to-head design owing to the rarity and severity of haemophilia A. There is some uncertainty in our findings, particularly in the estimated ABRs at Ctrough,ss of 30 µg/mL and 50 µg/mL, as a consequence of limited availability of data at lower and higher emicizumab concentrations. A search in the database in January 2021 identified at least three relevant ongoing studies on the PK of emicizumab (i.e., HAVEN 5−7), of which two are still recruiting PwHA. Therefore, it is certain that the present review will require an update in the near future. Another difficulty was the risk of bias assessment in the studies included due to a lack of standardized tools for such PK studies, in contrast to the quality assessment tools used for (randomized) clinical studies. However, the data used were considered methodologically sound, as PK parameters are objective measurements, studies were included using a systematic PRISMA search approach, and we only used for the Emax model negative binomial mean