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 15^th 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).
Linear dose-concentration relationship of emicizumab in people with hemophilia AEmax model with concentration-response relationship of emicizumab in people with hemophilia A

Conclusions: This systematic review supports body-weight-based dosing of emicizumab in PwHA. Individualized dosing by monitoring the concentration may be more cost-effective.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/a-systematic-review-on-the-pharmacokinetics-and-associated-pharmacodynamics-of-emicizumab-in-humans/