Pharmacokinetics and Associated Efficacy of Emicizumab in Humans: A Systematic Review

Abstract

Introduction: Emicizumab is an effective new treatment option for people with hemophilia A (PwHA). The approved dosing regimens are based on body weight, without the necessity for laboratory monitoring. This assumes a clear dose-concentration-response relationship, with acceptable variability due to factors other than body weight. To investigate this assumption, a systematic review on the pharmacokinetics (PK) and associated efficacy of emicizumab in humans was conducted.

Methods: The EMBASE, Pubmed and CENTRAL databases were systematically searched to November 2020 to identify studies on the PK data of emicizumab in humans. Data on the study, population, PK and efficacy (annualized bleeding rate of treated [joint] bleeds) were extracted and synthesized, and exposure effects modeling was performed using non-linear least squares regression in a maximum effect (E_max) model.

Results: The 15 included studies reported on data for 140 volunteers and 467 PwHA, including children (0 to <12 years) and adolescents and adults (≥12 years), both with and without factor VIII (FVIII) inhibitors. Emicizumab demonstrated dose-linear PK. The interindividual variability of trough concentrations was moderate (32%) and was similar across various subgroups, such as FVIII inhibitor status, age group and dosing interval. 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.

Conclusion: This review supports body weight-based dosing, although individualized monitoring of emicizumab concentrations may allow for more cost-effective dosing.

Fig. 1

Linear dose–concentration relationship of emicizumab in PwHA. The mean or median C_trough,ss according to increasing doses of emicizumab per week (mg/kg/week). Q2W and Q4W intervals shown per week. Data from PwHA (n = 469) receiving multiple dose regimens were included (see footnote ‘a’ for 15 study subgroups, in electronic supplementary Table ST2). PwHA people with hemophilia A, C_trough,ss trough plasma concentration in steady-state conditions, Q2W 2-weekly dose interval, Q4W 4-weekly dose interval

Fig. 2

Trough concentrations of emicizumab with variability across various subgroups in PwHA. The weighted variability (%CV) of the C_trough,ss of emicizumab was similar across FVIII inhibitor status and across various dosing intervals, whereas children had slightly less variability than adults/adolescents. The overall weighted %CV was 32%. Data from PwHA (n = 469) receiving multiple dose regimens were included (see footnote ‘a’ for 15 study subgroups, in electronic supplementary Table ST2). PwHA people with hemophilia A, %CV percentage coefficient of variation, C_trough,ss trough plasma concentration in steady-state conditions, Q2W 2-weekly dose interval, Q4W 4-weekly dose interval

Fig. 3

E_max model with concentration–response relationship of emicizumab in PwHA. Fit of an E_max model of ABRs of treated bleeds according to the C_trough,ss of emicizumab in PwHA (n = 349), described by $\text{ABR}={\text{ABR}}_{\text{baseline}}\times \left(1-(\frac{(C_{\text{trough},\text{ss}}\times E_{max})}{({\text{C}}_{\text{trough},\text{ss}}+{\text{EC}}_{50})}\right)$. Included ABRs were model-based, estimated using negative binominal regression. The EC₅₀ was estimated at 1.47 µg/mL (SE 0.90) and the effectiveness plateau was established. The dashed line is the 95% confidence interval, and symbol size equals study size. Data from PwHA receiving maintenance were included (see footnote ‘b’ for 11 study subgroups, in electronic supplementary Table ST2). E_max maximum effect, PwHA people with hemophilia A, ABRs annualized bleeding rates, C_trough,ss trough plasma concentration in steady-state conditions, EC₅₀ half maximal effective concentration, SE standard error