Abstract Number: PB0682
Meeting: ISTH 2021 Congress
Background: Emicizumab is an effective, new treatment for people with hemophilia A (PwHA) and, comparable to other therapeutic monoclonal antibodies, its financial costs are substantial. The approved dosing regimens are body weight-based without the necessity of dose adjustments based on laboratory monitoring. This assumes a clear dose-concentration-response relationship with low variability due to other factors than body weight.
Aims: To investigate this assumption, a systematic review on the pharmacokinetics (PK) and associated pharmacodynamics (PD) of emicizumab in humans was conducted.
Methods: The database Embase, Pubmed and CENTRAL were searched up to November 15th 2020 to identify studies on PK data of emicizumab in humans. Study, subject, PK and PD outcome data were synthesized. Exposure-effect modelling was performed using non-linear least squares regression in an Emax model with trough plasma concentrations and annualized bleed rate (ABR) of treated bleeds, all model-based by means of binomial regression.
Results: The 15 included studies on PK of emicizumab in humans reported data on 140 volunteers and 467 PwHA including children (aged 0 to <12 years), adolescents/adults (>12 years), both with and without FVIII inhibitors. Emicizumab demonstrated a clear linear dose-concentration profile already at low doses of 0.3 mg/kg/week (Figure 1). The inter-individual variability of trough plasma concentrations was moderate (32%) and similar across various subgroups, such as FVIII inhibitor status, age, dose interval. The EC50 was estimated at 1.47 µg/ml in the Emax model. The effectiveness plateau of the concentration−response relationship was clearly established, and all ABR observations resided herein with mean trough concentrations of ~50 µg/ml. The control of treated bleeds did not further improve above emicizumab trough plasma concentrations of ~30 µg/ml, potentially enabling lower dosing in a considerable proportion of PwHA (Figure 2).
Conclusions: This systematic review supports body-weight-based dosing of emicizumab in PwHA. Individualized dosing by monitoring the concentration may be more cost-effective.
To cite this abstract in AMA style:Donners A, Rademaker C, Bevers L, Huitema A, Schutgens R, Egberts A, Fischer K. A Systematic Review on the Pharmacokinetics and Associated Pharmacodynamics of Emicizumab in Humans [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/a-systematic-review-on-the-pharmacokinetics-and-associated-pharmacodynamics-of-emicizumab-in-humans/. Accessed December 7, 2021.
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